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HuGE Review

 
 

This HuGE Review is published with modification in Am J Epidemiol. 2000 May 1;151(9):846-61.  PMID:  10791558; UI: 20250197.

N-Acetyltransferase Polymorphisms and Colorectal Cancer
print version

by:  N. Brockton 1, J. Little 1, L. Sharp 1, and S.C. Cotton1

1 Epidemiology Group, Department of Medicine & Therapeutics, University of Aberdeen, Foresterhill House Annex, Foresterhill, Aberdeen, Scotland, AB25 2ZD

Abbreviations
CI
CYP1A1
CYP1A2
GSTM1
GSTT1
NAT
NAT1
NAT2
NATP
RR 		confidence interval
cytochrome P4501A1
cytochrome P4501A2
glutathione S -transferase class M1
glutathione S -transferase class T1
N -acetyltransferase
N -acetyltransferase type 1
N -acetyltransferase type 2
N -acetyltransferase pseudogene
relative risk

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At-A-Glance

The two expressed genes coding for N-acetyltransferase activity, NAT1 and NAT2, are located on chromosome 8p21.3-23.1 and are polymorphic. Both enzymes are capable of N-acetylation and O-acetylation and N, O-acetylation and are implicated in the activation and detoxification of known carcinogens. Single base-pair substitutions in NAT2 tend to occur in combination with other substitutions within the gene. As yet, less work has been done to characterise NAT1 allelic variants. Various methods for the detection of the reported polymorphisms exist. It is important to select a method that is appropriate to the population being studied. The functional significance of many NAT allelic variants has not been determined. Geographical and ethnic variation in the frequency of NAT2 genotypes associated with fast or intermediate acetylation has been observed. Insufficient data for NAT1 genotypes are available to reveal a clear geographic pattern. No consistent association has been found between acetylator phenotype or genotype and colorectal cancer. The lack of consistency can in part be accounted for by methodological factors, including limited statistical power. Possible interactions between the NATgenes and either environmental exposures or other polymorphic genes encoding xenobiotic metabolising enzymes have been investigated only in a minority of these studies and these have lacked statistical power to detect interactions.

Gene

In humans, there are three N-acetyltransferase (NAT) loci: two expressed genes, NAT1 and NAT2 , and a pseudogene, N-acetyltransferase pseudogene (NATP) . Both expressed genes are 870 base-pair intron-less protein coding regions encoding 290 amino acid proteins (1) and are located on chromosome 8 (2) at 8p21.3-23.1 (3). 

The two isozymes use acetyl coenzyme A as a cofactor and function as phase II conjugating enzymes (4); they are capable of N-acetylation and O-acetylation and N, O-acetylation (5). N -acetylation is a detoxification pathway.
O-acetylation and N, O-acetylation occur in alternative metabolic pathways following activation by N -hydroxylation. The isozymes differ in their substrate specificities: isoniazid and sulphamethazine are NAT2-specific substrates; p-aminobenzoic acid and p-aminosalicylic acid are NAT1-specific substrates. Amongst the enzyme substrates are several carcinogenic compounds, many of which are present in cooked food and tobacco smoke (6). This has prompted speculation that the NAT enzymes and the genes encoding them may be involved in susceptibility to cancer including colorectal cancer because of the presence of carcinogenic heterocyclic amines in some cooked foods (7). 

NAT2 is primarily expressed in the liver, whereas NAT1 is primarily expressed at other sites, including the colon (8). In colon tissue removed from cadavers, the ratio of NAT1:NAT2 activity was found to change along the length of the intestine (9). Differences between the relative levels of isozyme activity were most marked in the distal colon in one individual; 50-70 fold higher NAT1 than NAT2 activity was observed.

Gene Variants

The polymorphic nature of human NAT was first described in 1953 (10); a proportion of individuals receiving isoniazid therapy suffered adverse neurologic side effects due to an accumulation of unmetabolized drug. Family pedigree studies confirmed the genetic basis of the variation (11). Specific single base-pair substitutions responsible for altered enzyme activity were first reported in 1990 (2).  

NAT2 allele classification and nomenclature  

Three NAT2 phenotypes have been described. The fast acetylation phenotype results from possession of two copies of the wild-type allele. If only one allele is wild-type, an intermediate phenotype is observed. Persons with the slow acetylators phenotype possess two mutated alleles. Many early studies did not distinguish between fast and intermediate acetylators, categorising both types of subjects as “fast acetylators”. 

The first NAT2 alleles described were termed M1, M2 and M3. M1 consisted of a transition at nucleotide 481 (C481T) together with T342C; M2 consisted of a transition of C282T and G590A; and M3 consisted of a transition of G857A. Alleles M1 and M2 accounted for 90% of the slow acetylators in the original study (12), which included 18 subjects phenotyped in vivo and 26 liver samples phenotyped in vitro . M3 was first described in Japan (13).  

The identification and characterisation of new allelic variants by many different laboratories gave rise to conflicting allele designations, which complicating the interpretation of earlier studies. The scheme suggested by Vatsis et al. (5),
(Table 1), provides a nomenclature of currently recognised NAT alleles and facilitates the inclusion of any further alleles. The use of this scheme has simplified the interpretation of more recent studies. According to this nomenclature (5), M1, M2 and M3 should now be termed NAT2 *5A, NAT2 *6A and NAT2 *7A respectively. 

Ten point mutations have been reported in NAT2 (5), each a single base-pair substitution. Many published reports have investigated only single mutations and have based allele designations on this. However, recent improvements in techniques for detecting individual polymorphic sites have shown that isolated single substitutions are uncommon; combinations of mutations are more common. Within certain populations, some substitutions have been consistently observed to co-segregate (e.g. C481T rarely occurs without T341C (14)) . 

Functional significance of NAT2 mutations  

The NAT2 alleles described so far may contain up to four of the ten reported mutations (5). The functional significance of most combinations is unknown. However, it is plausible that each combination might result in a different phenotype.  

The functional significance of the ten mutations is summarised in table 2 (12, 13, 15-19). Some of the mutations change the amino acid sequence of the resultant enzyme, but not all of these have been observed to alter phenotype
(e.g. A803G (19)). However, some mutations, however, have been consistently observed to reduce acetylation activity (e.g. T341C) (20). The functional effect on phenotype is due to impairment of the protein translation or stability; messenger ribonucleic acid (mRNA) levels are not altered (12). For several of the mutations, their designation as “fast” or “slow” is not yet definitive. 

The C481T transition does not change the amino acid sequence; however, it has always been found with other mutations. In populations of European origin, C481T most often occurs with the T341C and A803G ; when C481T is combined with T341C, enzyme activity is reduced. G191A was discovered due to phenotype/genotype discordance in African-American subjects (16). Site directed mutagenesis (serial replacement of nucleotides within the gene coding region) showed codon 64 to be highly conserved between species and is implicated as the active site for acetyl transfer (17). Disruption of this region has been demonstrated to abolish enzyme activity in vitro . 

In European populations, relatively high concordance between acetylator phenotype (for NAT2 specific substrates) and NAT2 gene mutations has been demonstrated (12, 21).  

NAT1 allele nomenclature  

The study by Weber et al. (22) revealed several allelic variants, NAT1 was assumed to be monomorphic. The original alleles, designated V 1 (wild-type), V 2 (T1088A and C1095A) and V 3 (C -344T, A-40T, a 9 base pair deletion between nucleotides 1065 and 1090, and C1095A), have now been incorporated into the Vatsis nomenclature (5) and redesignated NAT1 *4, NAT1 *10, and NAT1 *11 respectively. 

Functional significance of NAT1 alleles  

Inter-individual variation in NAT1 activity has been reported. In addition, a two-fold intra-individual variation in activity (in 75 peripheral blood samples) was observed over a ten week period (23). If this finding is confirmed, it might suggest that NAT1 is inducible by exposure to endogenous or exogenous factors. 

The functional significance of the NAT1 allelic variants has not been fully established. Mutations can both increase and decrease the acetylation capacity relative to the wild-type allele. On the basis of the studies published to date (24-26), NAT1 *4 is considered the wild-type. The alleles that are believed to increase NAT1 acetylation capacity are NAT1 *10, *21, *24, *25. Alleles NAT1*14, *15, *17, *19 and *22 give rise to enzymes with reduced or no detectable activity. Alleles NAT1 *11, *20 and *23 produce enzymes with acetylation capacity similar to that of NAT1 *4. The current allele designations refer mainly to single substitutions, insertions or deletions. It is possible that combinations of these substitutions will be found to occur; these combinations may have functional consequences. 

Population frequencies  

We searched Medline and EMBASE using the Medical Subject Heading “arylamine N -acetyltransferase” and the textwords “NAT”, “NAT1 ”, “NAT2 ” and “N -acetyltransferase”. We also used the Medical Literature Search procedure in the Office of Genomics and Disease Prevention at the Centres for Disease Control and Prevention
( Atlanta , Georgia ). In addition, we reviewed reference lists in published articles. We identified and critically appraised relevant articles. This section includes studies reporting phenotype and genotype references 7, 14, 16, 18, 21, 23, 27-95; Table 3, frequencies in a variety of individuals without cancer. Studies reporting only the frequency of individual mutations or alleles were excluded since phenotype cannot be imputed. 

In many published articles the studies subject selection criteria are not stated. When they were stated, the criteria were diverse. Some studies have included disease-free subjects matched to diseased patients on characteristics such as age and sex, others were based on hospitalised subjects, specific occupational groups or volunteers for whom recruitment procedure was not described. This made it difficult to determine the extent to which apparent geographic or ethnic variation reflected biological differences or methodological factors. For example, the lowest frequency of fast/intermediate NAT2 acetylation genotypes reported in Europe (12%) was based on specimens obtained from a cell bank in France (52); this frequency is substantially lower than the frequencies of 39% and 47% observed in other studies carried out in France (53, 54) and elsewhere in Europe. 

In most NAT2 genotype studies only a limited number of “indicator” mutations, thought to be tightly linked with other mutations and predictive of acetylator status, have been investigated. This is likely to have led to underestimation of the proportion of NAT2 slow acetylators. The designation of alleles according to the presence/absence of “indicator” mutations assumes particular patterns of linkage, which may not be tenable in other populations or ethnic groups. For example, the genotype-phenotype discordance observed for African-Americans and USA Hispanics may result from compound alleles that are different to those observed in other populations (14). 

The frequency of NAT2 genotypes associated with fast or intermediate acetylation varies markedly between, and to some extent within, continents. The highest frequency occurs in Asia , particularly in Japan (approximately 90%). The frequencies reported in other South-East Asian populations are 73% in Hong Kong (14), 72% in Malaysia (46) and 58% in Singapore (47). Studies carried out in other parts of Asia have reported lower frequencies: 32% in India (39), 37% in the United Arab Emirates (49) and 43% in Turkey (48). In most European populations, approximately 40% of study subjects have genotypes associated with fast or intermediate acetylation. Genotype frequencies within the USA vary by ethnic group: for white subjects frequencies are similar to European populations and for Asians these are similar to those populations in South-East Asia . The lowest frequencies which have been reported in two small African studies in which subject selection was not described (27). Interestingly, higher frequencies have been reported in African-Americans (14).  

All but three of the studies (83, 84, 88) of NAT phenotype used NAT2 substrates. The geographical variation in the frequency of the fast/intermediate NAT phenotype is generally consistent with that observed for NAT2 genotype. 

Few studies to date have investigated NAT1 genotype. So far, NAT1 *10 is the most common variant of those investigated. The reported frequency of wild-type homozygosity ranges from 24%-96%. In the UK alone, variation of 29%-96% was observed. The frequency of NAT1 wild-type homozygosity within a study depends upon the alleles investigated. Hubbard et al. (95) considered NAT1 *14 and NAT1 *15, whereas Bell et al. (25) examined NAT1 *3, NAT1 *10 and NAT1 *11. In the USA , the wild-type homozygote frequencies are 44%-62% among whites (35, 38) and, in the one reported study which published results, 24% in African-Americans (35). Studies carried out in Australia (23) and Japan (42) reported frequencies of 92% and 38% respectively.

Disease

Worldwide in 1996, an estimated 876,000 new cases of colorectal cancer occurred - 445,000 in males and 431,000 in females (96).  Less than one third of colorectal cancer cases occur in developing countries (97).  In developed countries colorectal cancer is the second most common cancer in both sexes (97). 

World age-standardised incidence rates are lowest, around 10 per 100,000 population per annum, in Africa, India, Thailand and in some Chinese populations (98).  The highest rates, more 40 per 100,000 in men and more 30 per 100,000 in women, are observed in North America, Northern Europe, Australia and New Zealand.  In many populations colorectal cancer incidence rates have been rising (99) with the greatest increases being observed in Japan. For example, in Miyagi, Japan, the rate among males increased from 19.7 per 100,000 in 1978-1981 to 41.5 per 100,000 in 1988-92 and the rate among females from 16.8 per 100,000 to 24.8 per 100,000 (98, 100). 

Less than 10% of colorectal cancers are believed to be due to recognised genetic syndromes (familial adenomatous polyposis and hereditary non-polyposis colorectal cancer) (101).  After exclusion of these syndromes, however, familial aggregation has been observed (102, 103), suggesting a role of genetic susceptibility in disease aetiology.  Results of migrant studies indicate that environmental factors have an important influence (104, 105).  Thus, this evidence suggests that the majority of cases are probably to be due to a combination of environmental or lifestyle exposures and genetic susceptibility. 

A high intake of vegetables is inversely associated with the risk of colorectal cancer and it is possible that increased intakes of fibre, starch and carotenoids are protective (106).  There is consistent evidence that the most physically active groups in the population are at lower risk (107).  On the basis of evidence from over 20 observational studies, it has been concluded that regular use of aspirin reduces risk (108). 

Increased risk has been associated with diets high in sugar, total and saturated fat, eggs and processed meat, although the evidence is inconsistent (106).  More consistent evidence exists for a positive association with red meat consumption (106), with increased risk possibly being due to exposure to heterocyclic aromatic amines formed when meat is cooked to pyrolytic temperatures (6), rather than to consumption of meat per se (109).  A recent large case-control study found that although “usual” dietary intake of heterocyclic amines was not associated with increased colon or rectal cancer risk, very high daily intake was (110).  A role for the N-acetyltransferase enzymes in the activation of heterocyclic aromatic amines has been proposed (109).  The N-acetyltransferase enzymes are also involved in the activation of aromatic amines (7) found in tobacco smoke (111).  While tobacco smoking has consistently been associated with adenomatous polyps, the evidence with regard to colorectal cancer is less strong (112).  While some recent large cohort studies have suggested that smoking may increase risk after a long latent period (113-116), this has not been a consistent finding (117).

Associations

The studies discussed in this section, and the following section, were identified using the search strategy described above with the addition of Medical Search Headings and text words relevant to colorectal cancer or polyps. These studies are summarised in Tables 4 and 5 (7, 8, 24, 25, 30, 31, 37, 38, 40, 66, 78, 81, 90, 95, 118-126). 

Until genotyping techniques were developed (2), investigations of the relation between acetylator status and colorectal cancer relied on phenotyping. Probe drugs such as isoniazid, sulphamethazine and caffeine were administered and the metabolites were measured by high performance liquid chromatography. If the probe drug was NAT2-specific (as it is for most studies), it would fail to account for NAT1 activity. NAT1 phenotyping has been done to validate genotyping or to investigate the effects of individual alleles but it has not been used in assessing the association between colorectal cancer and acetylator status. In case-control studies, phenotypic assessment of acetylation may be influenced by the disease status.  

Five studies have investigated the association between acetylator phenotype and colorectal cancer (Table 4) (7, 90, 119-121); two of them simultaneously investigated phenotype and colorectal adenomatous polyps (120, 121). Four of the five cancer studies (7, 90, 119, 120) and one of the polyp studies (120) used NAT2 specific probe drugs. Table 5 summarises data from eleven studies of the relation of NAT2 genotype to colorectal cancer (8, 25, 37, 38, 40, 66, 78, 81, 122, 123, 125, 126) and three studies of polyps. (24, 30, 31, 124)  The participants investigated by Lin et al.(24) overlap with those investigated by Probst-Hensch et al. (30, 124) Five cancer studies (25, 38, 95, 123, 125) and two polyp studies (24, 30) also investigated NAT1 genotype (Table 5). 

Colorectal neoplasia and acetylator phenotype  

The results of three of the four studies using NAT2 specific probe drugs suggested a positive association between fast acetylator phenotype and colorectal cancer (7, 119, 120). In the fourth study, no association with colorectal cancer was found (90). Roberts-Thompson et al. (120) also analysed a series of polyps; no association was found with the acetylator phenotype. Lang et al. (121) used caffeine, which is not an NAT2 specific substrate, to determine acetylator status; no association with cancer and polyps was found (relative risk (RR)=1.3 [95% confidence interval (CI) 0.8-2.3]).  

Colorectal cancer and NAT2 genotype  

In ten of the eleven studies of invasive colorectal cancer and NAT2 acetylator genotype (Table 5), no association with fast/intermediate acetylator genotype was observed. The remaining study reported a statistically significant positive association with fast acetylation genotypes (RR=2.0 95% CI [1.3-3.2]) (66). 

Several issues affect the interpretation of these studies. Two studies were based on tissue samples, obtained either at surgery (122) or from a tissue sample bank (8) . No association was apparent in either study. However, there was little information on the subjects from whom the samples were obtained and the number of samples was small (<50) which limited statistical power. The other studies were all based on at least 100 cases. However, the study in which a significant association was found was the smallest of these (66). In this study, controls were statistically significantly younger than cases; if NAT2 genotype were associated with survival, this may have biased the relative risk. In addition, the areas of residence of cases and controls differed (66). 

Three studies included controls who would be expected to have been representative of the population-at-risk of developing the disease (37, 38, 81). In the other studies, either the controls may not have been representative of the population-at-risk (8, 25, 66, 78, 122, 125) or the methods of control selection were not clearly described (40, 123).

The methods of case selecting varied between studies, possibly affecting their comparability. For example, Hubbard et al. (78) included operable cases and Bell et al. (25) included a “sample” of incident tumours. If the reasons for exclusion were related to disease aetiology or progression, this might have influenced the observed result. The study by Slattery et al. (37) related only to colon cancer, whereas the others also included rectal cancer (but would have had lower statistical power to investigate subsite-specific associations). 

Although one study (66) observed an association between colorectal cancer and NAT2 genotype, other studies have detected associations within subgroups. Hubbard et al. (78) reported a positive association between colorectal cancer and slow acetylation amongst subjects under seventy years (RR=1.7 95% CI [1.1-2.6]). In contrast, Slattery et al. (37) reported a positive association between colon cancer and fast/intermediate acetylator status among older women
( >67 years) (RR=1.4 95% CI [1.0-1.8]). In one study, data on specific NAT2 alleles were presented (125). There was a positive association between NAT2 *7A allele and colorectal cancer (RR=2.4 95% CI [1.5-3.9]). However, the interpretation of this finding is limited by the potential selection bias noted above. 

Colorectal cancer and NAT1 genotype  

Investigations of NAT1 and colorectal cancer were prompted by observations that NAT1 is expressed to a greater extent than NAT2 in the colon. It would therefore be expected that localised activation of the heterocyclic or aromatic amines within the colon would be predominantly due to NAT1 (8, 9). The low frequency of some NAT1 allelic variants could result in limited statistical power to detect any effect. 

An association between NAT1 and colorectal cancer was observed in only one (25) of five studies (Table 5). That study investigated a limited selection of the most common alleles and found a statistically significant increased risk associated with NAT1 *10 (RR=1.9 95% CI [1.2-3.1]). These investigators had previously demonstrated that NAT1 *10 was associated with higher acetylation activity in colon tissue (127). In the studies by Chen et al. (38) and Lee et al. (125), genotypes were assigned on the basis of the alleles investigated by Bell et al. (25). Jenkins et al. (123) did not specify the alleles investigated and Hubbard et al. (95) only investigated two relatively uncommon alleles. 

Colorectal cancer and combined NAT1 and NAT2 genotypes  

Five studies that determined NAT1 and NAT2 genotypes also investigated the effect of combinations of these genotypes (25, 38, 95, 123, 125). None reported any increased risk associated with any combination of NAT1/NAT2 genotypes. However, the statistical power to investigate some of these combinations would have been low. In addition, the limitations regarding study design of alleles detected discussed above also apply. 

Colorectal polyps and acetylator genotype  

Three studies have investigated the relationship between colorectal polyps and aspects of NAT genotype (Table 5; 24, 30, 31, 124). No association was found between NAT1 or NAT2 genotype and adenomas. However, an association between NAT1 *10 and risk was found when the cases were restricted to “incident” adenomas (i.e. those with negative sigmoidoscopy results within the previous five years) (30). Subjects were recruited from persons undergoing sigmoidoscopy. It is possible that some of the controls may have harboured adenomatous polyps out of reach of the sigmoidoscope. This would have biased any association with NAT genotypes towards the null. Probst-Hensch et al. (30) suggested that the lack of an overall association might reflect the presence of undetected NAT1 mutations. However, the results of subsequent re-analysis (24) in which the NAT1 gene was screened for mutations but no association between genotype and disease was found, make this unlikely. One study analysed separately individuals with hyperplastic polyps only (31). No association was found between NAT2 genotype and disease.  

Comment on inconsistency between phenotype and genotype studies  

Overall the studies involving assessment of genotype provide little evidence of an association between acetylator status and risk of colorectal lesions. However, the studies of phenotype suggest a positive association between fast acetylation and disease risk. This inconsistency could be due to discordance between genotype and phenotype. As suggested above, the designation of the NAT2 and NAT1 genotypes to imputed phenotype is not yet definitive. Discrepancies between genotype and phenotype have been observed in approximately 5-7% of subjects assessed in studies of European populations (128). However, fast acetylation status per se would not be expected to raise risk in the absence of exposure to NAT substrates, therefore it is likely that the genotyping studies more accurately reflect risk attributable to acetylation status alone. The explanation for the increased risk observed in the phenotype studies is not clear, but possible contributing factors include: alteration of acetylation phenotype by the presence of disease; selection or participation bias of cases and/or controls; confounding of phenotype by exposures which cause colorectal cancer and chance.

Interactions

It would not necessarily be expected that NAT genotype would be independently associated with risk of colorectal neoplasia. If the NAT genes have a role in the aetiology of colorectal neoplasia, it is likely that it is as a modifier of the relationships between particular environmental exposures and disease. Mechanisms by which environmental exposures might lead to malignancy, involving NATs, other enzymes and concomitant exposure to their substrates, have been proposed (129).  

The NAT substrates are also substrates for other enzymes in the putative detoxification/activation pathways of aromatic amines (129). A substrate may be either hydroxylated or N-acetylated by cytochrome P450 or NAT respectively. The hydroxylated substrate may undergo O-acetylation catalysed by NAT. The metabolic fate of each substrate depends upon the relative activity, specificity and affinity of the enzymes in these competing pathways towards that substrate. It is not clear at present how the metabolic fate of specific substrates may be affected by the various allelic forms of the NAT genes. 

Of the eleven studies of colorectal cancer and NAT2 genotypes, only three assessed possible exposure of both cases and controls to NAT substrates and analysed this together with genotype (37, 38, 81); one other study provided genotype-exposure data for cases only (25). The three studies investigating colorectal adenomas all collected exposure data (24, 30, 124); however, only one analysed this with genotype (124). Most of the studies which have investigated interactions have had relatively small numbers of subjects in the acetylator status-environmental exposure subgroups, which limited statistical power to detect an interaction should one have been present. 

NAT genotype and dietary exposures

The joint effects of dietary exposure and NAT genotype were investigated in three studies (38, 81, 126). Among NAT2 fast acetylators, Welfare et al. (81) found a significantly raised risk of colorectal cancer associated with consumption of fried meat more than twice weekly, as compared with less frequent consumption (RR=6.0 95% CI [1.3-55.0]). This was not found among slow acetylators. In the study by Chen et al. (38), among fast acetylators (based on combined NAT1*10 and fast/intermediate NAT2 genotypes) the relative risks for >0.5-1 and >1 daily servings of red meat versus £ 0.5 daily servings were modestly, but non-significantly, raised (>0.5-1 daily servings: RR=2.1 95% CI [0.81-5.65]; >1 daily servings: RR=2.4 95% CI [0.77-7.12]). This was not seen in non-fast acetylators. This pattern was more pronounced among subjects aged >60 years. However, the test for interaction was not statistically significant either for subjects of all ages (p=0.16) or for older subjects (p=0.25). The method by which the red meat was cooked was not reported nor was the preference for well-done meat. 

Kampman et al. (126), in further analysis of the subjects included in the study by Slattery et al. (37), investigated associations between various measures of meat consumption, NAT2 genotype and colon cancer. Among persons with the intermediate/rapid genotype, there were modestly raised risks associated with (1) higher consumption of red meat, (2) preference for well done red meat, (3) high levels of a red meat mutagen index, (4) higher consumption of processed meat and (5) higher levels of a total meat mutagen index. Unexpectedly, consumption of white meat was more strongly associated with risk among slow acetylators, but the relative risks were only modestly raised. 

NAT phenotype and dietary exposures

Two studies have investigated interactions between acetylator phenotype and diet and risk of colorectal lesions, with inconsistent results (118, 120). Wohlleb et al. (118) modelled various aspects of diet, phenotype and colorectal cancer risk. While consumption of luncheon meat and pork were each significantly associated with disease risk; the introduction of acetylator status into the model had no significant effect.  

Roberts-Thomson et al. (120) stratified subjects into slow and fast acetylator phenotype groups and assessed the linear trend in risk of (1) adenoma and (2) cancer across three categories of meat intake (low, medium and high) in the two strata. It is not clear how these categories of meat intake were determined. Among slow acetylators, there was no association between meat intake and risk of adenoma. Among fast acetylators, adenoma risk increased with increasing meat consumption (continuous variable RR=2.1 95% CI [0.9-4.7]; p for linear trend=0.08). For colorectal cancer, among slow acetylators the relative risk did not differ significantly from 1 across the categories of meat intake. Among fast acetylators, cancer risk increased with meat intake (continuous variable RR=1.7 95% CI [0.9-3.5]; p for linear trend=0.13). 

NAT genotype and smoking

The possibility of an interaction between NAT genotype and smoking was assessed in four studies (31, 37, 81, 124), with inconsistent results. Slattery et al. (37) found a modest association between several measures of tobacco exposure and colon cancer in men and women but this effect was modified only slightly by NAT2 genotype. 

In their study of hyperplastic polyps and adenomas, Potter et al. (31) also found significant association between smoking status and pack years of smoking and both types of polyps, but these associations were not modified by NAT2 genotype. Welfare et al. (81) reported that cigarette smoking in the past five years was not associated with cancer risk among NAT2 fast acetylators, but it was associated with significantly raised risk among slow acetylators (RR=2.3 95% CI [1.2-4.6]). 

In their study of adenomas, Probst-Hensch et al. (124) observed a raised risk in current smokers who were NAT2 fast acetylators, in comparison with persons who had never smoked and were slow acetylators (RR=2.3 95% CI [1.0-5.2]). Consistent with this, in an analysis of colorectal cancer cases only, NAT1 *10 was found to occur more frequently among smokers (52%) than among non-smokers (41%) (25). NAT2 fast acetylator genotypes were also more common among smokers (52%) than non-smokers (45%).  

NAT genotype and other genes

Other enzymes in the detoxification/activation pathway are also polymorphic. For example, the glutathione S-transfearse class M1 (GSTM1) and glutathione S-transfearse class T1 (GSTT1) genes, involved in detoxification, are polymorphic (130), functionally significant alleles of cytochrome P4501A1 (CYP1A1) have been reported (131) and genetic polymorphism in cytochrome P4501A2 (CYP1A2) has recently been demonstrated (132, 133). This raises the possibility that these genes may interact to affect disease risk. Gene-gene-environment interactions have been investigated in three studies (37, 121, 124).  

Slattery et al. (37) stratified their subjects by joint GSTM1 and NAT2 genotype and investigated colon cancer risk associated with smoking within each stratum. Among men who were NAT2 -slow and GSTM1 -null, the relative risks associated with smoking <20 and >20 cigarettes a day, compared with not smoking, were 1.4 95% CI [0.8-2.3] and 1.7 95% CI [1.2-2.6] respectively. This trend was not observed in other genotype strata, or among women. Probst-Hensch et al. (124) reported a significantly raised risk of adenomas for fast acetylators who were GSTM1-null in comparison to slow acetylators who were GSTM1 -non-null, among current smokers (RR=10.3 95% CI [1.94-55.0]). This genotype combination was not associated with raised risk among never smokers (RR=1.0 95% CI [0.5-2.2]). 

Lang et al. (121) considered the joint effects of NAT2 phenotype, CYP1A2 phenotype (rapid or slow) and meat cooking preference (rare/medium or well-done) on the risk of colorectal cancer and polyps combined. The reference category comprised subjects who were NAT2 -slow, CYP1A2 -slow and preferred rare/medium meat. The relative risk for subjects who were NAT2 -rapid/CYP1A2 -rapid and preferred rare/medium meat was 3.1 and the relative risk for subjects who were NAT2 -rapid/CYP1A2 -rapid and preferred well-done meat was 6.5. Confidence intervals were not reported. The result for the test for interaction was not significant. It is likely that each stratum contained few subjects.

Laboratory Tests

Early case-control studies on acetylation and colorectal cancer used phenotyping methodologies (Table 4). The NAT genotyping techniques currently used in epidemiological studies rely on initial amplification of the region of the gene in which the polymorphisms are found. Following amplification, restriction fragment length polymorphism (RFLP) analysis and allele-specific polymerase chain reaction (PCR) are most commonly used. An oligo-ligation assay has recently been developed and it is particularly suitable for automated studies (134).

Because of the marked inter-ethnic differences in NAT genotypes, it is important that the appropriate mutations be investigated so that alleles can be assigned correctly. Failure to fully define alleles may bias the estimate of imputed acetylator phenotype. For example, Lin et al. (24) re-analysed samples from the study by Probst-Hensch et al. (124) and re-categorised twenty subjects, who had been classified as “fast” in the original study, as slow acetylators. In addition, if additional substitutions are not explicitly detected by the techniques employed, but are assumed to be present due to previously observed linkage patterns, it is important that this be explicitly stated in the characterisation of the alleles.

Population Testing

There is currently insufficient evidence implicating polymorphic NAT genes in the aetiology of colorectal cancer or adenomatous polyps to justify population testing.

 References

  1. Ebisawa T, Deguchi T. Structure and restriction fragment length polymorphism of genes for human liver arylamine N-acetyltransferases. Biochemical and Biophysical Research Communications 1991;177:1252-7.
  2. Blum M, Grant DM, McBride W, et al. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA and Cell Biology 1990;9:193-203.
  3. Hickman D, Risch A, Buckle V, et al. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochemical Journal 1994;297:441-5.
  4. Smith CAD, Smith G, Wolf CR. Genetic polymorphisms in xenobiotic metabolism. European Journal of Cancer 1994;30A:1921-1935.
  5. Vatsis KP, Weber WW, Bell DA, et al. Nomenclature for N-acetyltransferases. Pharmacogenetics 1995;5:1-17.
  6. Sinha R, Rothman N, Brown ED, et al. Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans. Cancer Research 1994;54:6154-9.
  7. Lang NP, Chu DZJ, Hunter CF, et al. Role of aromatic amine acetyltransferase in human colorectal cancer. Archives of Surgery 1986;121:1259-61.
  8. Rodriguez JW, Kirlin WG, Ferguson RJ, et al. Human acetylator genotype: relationship to colorectal cancer incidence and arylamine N-acetyltransferase expression in colon cytosol. Archives of Toxicology 1993;67:445-52.
  9. Hickman D, Pope J, Patil SD, et al. Expression of arylamine N-acetyltransferase in human intestine. Gut 1998;42:402-9.
  10. Bönicke R, Reif W. Enzymatic inactivation of isonicotinic acid hydrazide in humans and animals. Arch Exp Pathol Pharmak 1953;220:321-33.
  11. Evans DAP, Manley KA, McKusick VA. Genetic control of isoniazid metabolism in man. British Medical Journal 1960;2:485-91.
  12. Blum M, Demierre A, Grant DM, et al. Molecular mechanism of slow acetylation of drugs and carcinogens in humans. Proceedings of the National Academy of Sciences of United States of America 1991;88:5237-41.
  13. Ohsako S, Deguchi T. Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. Journal of Biological Chemistry 1990;265:4630-4.
  14. Lin HJ, Han CY, Lin BK, et al. Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, Blacks, Hispanics, and Whites: Application to metabolic epidemiology. American Journal of Human Genetics 1993;52:827-34.
  15. Woolhouse NM, Qureshi MM, Bayoumi RAL. A new mutation C759T in the polymorphic N-acetyltransferase (NAT2) gene. Pharmacogenetics 1997;7:83-4.
  16. Bell DA, Taylor JA, Butler MA, et al. Genotype/phenotype discordance for human arylamine N-acetyltransferase (NAT2) reveals a new slow-acetylator allele common in African-Americans. Carcinogenesis 1993;14:1689-92.
  17. Deloménie C, Goodfellow GH, Krishnamoorthy R, et al. Study of the role of the highly conserved residues Arg9 and Arg64 in the catalytic function of human N-acetyltransferases NAT1 and NAT2 by site-directed mutagenesis. Biochemical Journal 1997;323:207-15.
  18. Lin HJ, Han CY, Lin BK, et al. Ethnic distribution of slow acetylator mutations in the polymorphic N-acetyltransferase (NAT2) gene. Pharmacogenetics 1994;4:125-34.
  19. Cascorbi I, Brockmöller J, Bauer S, et al. NAT2*12A (803A®G) codes for rapid arylamine N-acetylation in humans. Pharmacogenetics 1996;6:257-9.
  20. Hein DW, Doll MA, Rustan TD, et al. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Research 1995;55:3531-3536.
  21. Smith CAD, Wadelius M, Gough AC, et al. A simplified assay for the arylamine N-acetyltransferase 2 polymorphism validated by phenotyping with isoniazid. Journal of Medical Genetics 1997;34:758-60.
  22. Weber WW, Vatsis KP. Individual variability in p-aminobenzoic acid N-acetylation by human N-acetyltransferase (NAT1) of peripheral blood. Pharmacogenetics 1993;3:209-12.
  23. Butcher N, Ilett K, Minchin R. Intra- and inter-individual differences in N-acetyltransferase type 1 activity in human peripheral blood mononuclear cells. Proceedings of the American Association for Cancer Research 1997;38:338.
  24. Lin HJ, Probst-Hensch NM, Hughes NC, et al. Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas. Pharmacogenetics 1998;8:269-81.
  25. Bell DA, Stephens EA, Castranio T, et al. Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. Cancer Research 1995;55:3537-42.
  26. Hughes NC, Janezic SA, McQueen KL, et al. Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe. Pharmacogentics 1998; 8:55-56.
  27. Deloménie C, Sica L, Grant DM, et al. Genotyping of the polymorphic N-acetyltransferase (NAT2*) gene locus in two native African populations. Pharmacogenetics 1996;6:177-85.
  28. Martínez C, Agúndez JAG, livera M, et al. Influence of genetic admixture on polymorphisms of drug-metabolizing enzymes: analyses of mutations on NAT2 and CYP2E1 genes in a mixed Hispanic population. Clinical Pharmacology and Therapeutics 1998;63:623-8.
  29. Hunter DJ, Hankinson SE, Hough H, et al. A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis 1997;18:2127-32.
  30. Probst-Hensch NM, Haile RW, Li DS, et al. Lack of association between the polyadenylation polymorphism in the NAT1 (acetyltransferase 1) gene and colorectal adenomas. Carcinogenesis 1996;17:2125-9.
  31. Potter JD, Bigler J, Fosdick L, et al. Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase 2 polymorphisms. Cancer Epidemiology, Biomarkers and Prevention 1999;8:69-75.
  32. Ambrosone CB, Freudenheim JL, Graham S, et al. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. Journal of the American Medical Association 1996;276:1494-501.
  33. Mendola P, Moysich KB, Freudenheim JL, et al. Risk of recurrent spontaneous abortion, cigarette smoking, and genetic polymorphisms in NAT2 and GSTM1. Epidemiology 1998;9:666-8.
  34. Hirvonen A, Taylor JA, Wilcox A, et al. Xenobiotic metabolism genes and the risk of recurrent spontaneous abortion. Epidemiology 1996;7:206-8.
  35. Millikan RC, Pittman GS, Newman B, et al. Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiology, Biomarkers and Prevention 1998;7:371-8.
  36. Trizna Z, de Andrade M, Kyritsis AP, et al. Genetic polymorphisms in glutathione S-transferase mu and theta, N-acetyltransferase, and CYP1A1 and risk of gliomas. Cancer Epidemiology, Biomarkers and Prevention 1998;7:553-5.
  37. Slattery ML, Potter JD, Samowitz W, et al. NAT2, GSTM-1, cigarette smoking, and risk of colon cancer. Cancer Epidemiology, Biomarkers and Prevention 1998;7:1079-84.
  38. Chen J, Stampfer MJ, Hough HL, et al. A prospective study of N-acetyltransferase genotype, red meat intake, and risk of colorectal cancer. Cancer Research 1998;58:3307-11.
  39. Rothman N, Talaska G, Hayes RB, et al. Acidic urine pH is associated with elevated levels of free urinary benzidine and N-acetylbenzidine and urothelial cell DNA adducts in exposed workers. Cancer Epidemiology, Biomarkers and Prevention 1997;6:1039-42.
  40. Shibuta K, Nakashima T, Abe M, et al. Molecular genotyping for N-acetylation polymorphism in Japanese patients with colorectal cancer. Cancer 1994;74:3108-12.
  41. Asada M, Goto H, Abe M, et al. N-Acetylation polymorphism in Japanese patients with sarcoidosis. Pharmacogenetics 1997;7:341-4.
  42. Katoh T, Kaneko S, Boissy R, et al. A pilot study testing the association between N-acetyltransferases 1 and 2 and risk of oral squamous cell carcinoma in Japanese people. Carcinogenesis 1998;19:1803-7.
  43. Okumura K, Kita T, Chikazawa S, et al. Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism. Clinical Pharmacology and Therapeutics 1997;61:509-17.
  44. Oyama T, Kawamoto T, Mizoue T, et al. N-acetylation polymorphism in patients with lung cancer and its association with p53 gene mutation. Anticancer Research 1997;17:577-82.
  45. Morita S, Yano M, Tsujinaka T, et al. Association between genetic polymorphisms of glutathione S-transferase P1 and N-acetyltransferase 2 and susceptibility to squamous-cell carcinoma of the esophagus. International Journal of Cancer 1998;79:517-20.
  46. Zhao B, Lee EJD, Wong JYY, et al. Frequency of mutant CYP1A1, NAT2 and GSTM1 alleles in normal Indians and Malays. Pharmacogenetics 1995;5:275-80.
  47. Lee EJD, Zhao B, Seow-Choen F. Relationship between polymorphism of N-acetyltransferase gene and susceptibility to colorectal carcinoma in a Chinese population. Pharmacogenetics 1998;8:513-7.
  48. Aynacioglu AS, Cascorbi I, Mrozikiewicz PM, et al. Arylamine N-acetyltransferase (NAT2) genotypes in a Turkish population. Pharmacogenetics 1997;7:327-31.
  49. Woolhouse NM, Qureshi MM, Bastaki SMA, et al. Polymorphic N-acetyltransferase (NAT2) genotyping of Emiratis. Pharmacogenetics 1997;7:73-82.
  50. Nielsen PS, de Pater N, Okkels H, et al. Environmental air pollution and DNA adducts in Copenhagen bus drivers – Effect of GSMT1 and NAT2 genotypes on adduct levels. Carcinogenesis 1996;17:1021-7.
  51. Okkels H, Sigsgaard T, Wolf H, et al. Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) polymorphisms in susceptibility to bladder cancer: the influence of smoking. Cancer Epidemiology, Biomarkers and Prevention 1997;6:225-31.
  52. Muiras ML, Verasdonck P, Cottet F, et al. Lack of association between human logevity and genetic polymorphisms in drug-metabolizing enzymes at the NAT2, GSTM1 and CYP2D6 loci. Human Genetics 1998;102:526-32.
  53. Bendriss EK, Bechtel YC, Paintaud G, et al. Acetylation polymorphism expression in patients before and after liver transplantation: influence of host/graft genotypes. Pharmacogenetics 1998;8:201-9.
  54. Bouchardy C, Mitrunen K, Wikman H, et al. N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk. Pharmacogenetics 1998;8:291-8.
  55. Cascorbi I, Drakoulis N, Brockmöller J, et al. Arylamine N-acetyltransferase (NAT2) mutations and their allelic linkage in unrelated caucasian individuals: correlation with phenotypic activity. American Journal of Human Genetics 1995;57:581-92.
  56. Schnakenberg E, Ehiers C, Feyerabend W, et al. Genotyping of the polymorphic N-acetyltransferase (NAT2) and loss of heterozygosity in bladder cancer patients. Clinical Genetics 1998;53:396-402.
  57. Cascorbi I, Brockmoller J, Mrozikiewicz PM, et al. Homozygous rapid arylamine N-acetyltransferase (NAT2) genotype as a susceptibility factor for lung cancer. Cancer Research 1996;56:3961-6.
  58. Brockmöller J, Cascorbi I, Kerb R, et al. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase and cytochrome P450 enzymes as modulators of bladder cancer risk. Cancer Research 1996;56:3915-25.
  59. Bartsch H, Malaveille C, Lowenfels AB, et al. Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase in relation to malignant and benign pancreatic disease risk. European Journal of Cancer Prevention 1998;7:215-23.
  60. Gabbani G, Nardini B, Bordin A, et al. Urinary mutagenicity on TA98 and YG1024 Salmonella typhimurium strains after a hamburger meal: influence of GSTM1 and NAT2 genotypes. Mutagenesis 1998;13:187-91.
  61. Dallinga JW, Pachen DM, Wijnhoven SW, et al. The use of 4-aminobiphenyl hemoglobin adducts and aromatic DNA adducts in lymphocytes of smokers as biomarkers of exposure. Cancer Epidemiology, Biomarkers and Prevention 1998;7:571-7.
  62. Zielinska E, Niewiarowski W, Bodalski J, et al. Arylamine N-acetyltransferase (NAT2 ) gene mutations in children with allergic diseases. Clinical Pharmacology and Therapeutics 1997;62:635-42.
  63. Mrozikiewicz PM, Cascorbi I, Brockmoller J, et al. Determination and allelic allocation of seven nucleotide transitions within the arylamine N-acetyltransferase gene in the Polish population. Clinical Pharmacology and Therapeutics 1996;59:376-82.
  64. Zielinska E, Niewiarowski W, Bodalski J, et al. Genotyping of the arylamine N-acetyltransferase polymorphism in the prediction of idiosyncratic reactions to trimethoprim-sulfamethoxazole in infants. Pharmacy World and Science 1998;20:123-30.
  65. Lemos MC, Fegateiro FJ. N-acetyltransferase genotypes in the Portuguese population. Pharmacogenetics 1998;8:561-4.
  66. Gil JP, Lechner MC. Increased frequency of wild-type arylamine-N-acetyltransferase allele NAT2*4 homozygotes in Portuguese patients with colorectal cancer. Carcinogenesis 1998; 19:37-41.
  67. Kalina I, Gajdosová D, Binková B, et al. Cytogenic monitoring in coke oven workers. Mutation Research 1998;417:9-17.
  68. Binková B, Topinka J, Mracková G, et al. Coke oven workers study: the effect of exposure and GSTM1 and NAT2 genotypes on DNA adduct levels in white blood cells and lymphocytes as determined by 32P-postlabelling. Mutation Research 1998;416:67-84.
  69. Agúndez JAG, Ladero JM, Olivera M, et al. Genetic analysis of the arylamine N-Acetyltransferase polymorphism in breast cancer patients. Oncology 1995;52:7-11.
  70. Martinez C, Agúndez JAG, Olivera M, et al. Lung cancer and mutations at the polymorphic NAT2 gene locus. Pharmacogenetics 1995;5:207-14.
  71. Agúndez JAG, Olivera M, Ladero JM, et al. Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics 1996;6:501-12.
  72. Agúndez JAG, Menaya JG, Tejeda R, et al. Genetic analysis of the NAT2 and CYP2D6 polymorphisms in white patients with non-insulin-dependent diabetes mellitus. Pharmacogenetics 1996;6:465-72.
  73. Agúndez JAG, Rodríguez I, Olivera M, et al. CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians. Age and Ageing 1997;26:147-51.
  74. Agúndez JAG, Martinez C, Olivera M, et al. Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk. British Journal of Cancer 1998;78:1356-60.
  75. Agúndez JAG, Jiménez-Jiménez FJ, Luengo A, et al. Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson's disease. Neurology 1998;51:1587-92.
  76. Dalene M, Jakobsson K, Rannug A, et al. MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation. International Archives of Occupational and Environmental Health 1996;68:165-9.
  77. Nyberg F, Hou SM, Hemminki K, et al. Glutathione S-Transferase m1 and N-Acetyltransferase 2 genetic polymorphisms and exposure to tobacco smoke in nonsmoking and smoking lung cancer patients and population controls. Cancer Epidemiology, Biomarkers and Prevention 1998;7:875-83.
  78. Hubbard AL, Harrison DJ, Moyes C, et al. N-acetyltransferase 2 genotype in colorectal cancer and selective gene retention in cancers with chromosome 8p deletions. Gut 1997;41:229-34.
  79. Bandmann O, Vaughan J, Holmans P, et al. Association of slow acetylator genotype for N-acetyltransferase 2 with familial Parkinson's disease. Lancet 1997;350:1136-9.
  80. Risch A, Smelt V, Lane D, et al. Arylamine N-acetyltransferase in erythrocytes of cystic fibrosis patients. Pharmacology and Toxicology 1996;78:235-40.
  81. Welfare MR, Cooper J, Bassendine MF, et al. Relationship between acetylator status, smoking, diet and colorectal cancer risk in the north-east of England. Carcinogenesis 1997;18:1351-4.
  82. Parkin DP, Vandenplas S, Botha FJH, et al. Trimodality of isoniazid elimination. Phenotype and genotype in patients with tuberculosis. American Journal of Respiratory and Critical Care Medicine 1997;155:1717-22.
  83. Kirlin WG, Ogolla F, Andrews AF, et al. Acetylator genotype-dependent expression of arylamine N-acetyltransferase in human colon cytosol from non-cancer and colorectal cancer patients. Cancer Research 1991;51:549-55.
  84. Rothman N, Bhatnagar VK, Hayes RB, et al. The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial NDA adducts in exposed workers. Proceedings of the National Academy of Sciences of United States of America 1996;93:5084-9.
  85. Koizumi A, Nomlyama T, Tsukada M, et al. Evidence on N-acetyltransferase allele-associated metabolism of hydrazine in Japanese workers. Journal of Occupational and Environmental Medicine 1998;40:217-22.
  86. Bulovskaya LN, Krupkin RG, Bochina TA, et al. Acetylator phenotype in patients with breast cancer. Oncology 1978;35:185-8.
  87. Sardas S, Çok I, Sardas OS, et al. Polymorphic N-acetylation capacity in breast cancer patients. International Journal of Cancer 1990;46:1138-9.
  88. Schnuch A, Wstphal GA, Müller MM, et al. Genotype and phenotype of N-acetyltransferase 2 (NAT2) polymorphism in patients with contact allergy. Contact Dermatitis 1998;38:209-11.
  89. Ladero JM, Fernández MJ, Palmeiro R, et al. Hepatic acetylator polymorphism in breast cancer patients. Oncology 1987;44:341-4.
  90. Ladero JM, González JF, Benítez J, et al. Acetylator polymorphism in human colorectal carcinoma. Cancer Research 1991;51:2098-100.
  91. Webster DJT, Flook D, Jenkins J, et al. Drug acetylation in breast cancer. British Journal of Cancer 1989;60:236-7.
  92. Cartwright RA, Glashan RW, Rogers HJ, et al. Role of N-acetyltransferase phenotypes in bladder carcinogenesis: A pharmacogenetic epidemiological approach to bladder cancer. Lancet 1982;2:842-6.
  93. Philip PA, Rogers HJ, Millis RR, et al. Acetylator status and its relationship to breast cancer and other diseases of the breast. European Journal of Cancer and Clinical Oncology 1987;23:1701-6.
  94. Ilett KF, Detchon P, Ingram DM, et al. Acetylation phenotype is not associated with breast cancer. Cancer Research 1990;50:6649-51.
  95. Hubbard AL, Moyes C, Wyllie AH, et al. N-acetyl transferase 1: two polymorphisms in coding sequence identified in colorectal cancer patients. British Journal of Cancer 1998;77:913-6.
  96. WHO (World Health Organization). Conquering suffering, enriching humanity. Report No. WHO/WHR/97. Geneva: World Health Organization, 1997.
  97. Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. International Journal of Cancer 1993;54:594-606.
  98. Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five Continents. Volume VII. Lyon: IARC, 1997.
  99. Coleman MP, Estève J, Damiecki P, et al. Trends in Cancer Incidence and Mortality. Lyon: IARC, 1993.
  100. Muir C, Waterhouse J, Mack T, et al. Cancer incidence in five continents. Volume V. Lyon: IARC, 1987.
  101. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. Journal of the National Cancer Institute 1995;87:1114-25.
  102. St. John DJB, McDermott FT, Hopper JL, et al. Cancer risk in relatives of patients with common colorectal cancer. Annals of Internal Medicine 1993;118:785-90.
  103. Fuchs CS, Giovannucci EL, Colditz GA, et al. A prospective study of family history and the risk of colorectal cancer.  New England Journal of Medicine 1994;331:1669-74.
  104. Haenszel W, Kurihara M. Studies of Japanese migrants: mortality from cancer and other diseases among Japanese in the United States. Journal of the National Cancer Institute 1968;40:43-68.
  105. Schottenfeld D, Winawer SJ. Cancers of the large intestine. In Schottenfeld D, Fraumeni JF, Jr. eds. Cancer Epidemiology and Prevention. New York: Oxford University Press, 1996:813-40.
  106. World Cancer Research Fund in Association with American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: a global perspective. Menasha: American Institute for Cancer Research, 1997.
  107. Surgeon General. Physical Activity and Health. A Report of the Surgeon General.  Washington, D.C.: US Department of Health and Human Services. 1996.
  108. IARC Working Group. IARC Handbook of Cancer Prevention, Volume 1: Non-Steroidal Anti-Inflammatory Drugs. Lyon: IARC, 1997.
  109. Vineis P, McMichael A. Interplay between heterocyclic amines in cooked meat and metabolic phenotype in the etiology of colon cancer. Cancer Causes and Control 1996;7:479-86.
  110. Augustsson K, Skog K, Jägerstad M, et al. Dietary heterocyclic amines and cancer of the colon, rectum, bladder, and kidney: a population-based study. Lancet 1999;353:703-707.
  111. IARC Working Group. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans Volume 38. Tobacco Smoking. Lyon: IARC, 1986.
  112. Cotton S, Sharp L, Little J. The adenoma-carcinoma sequence and prospects for the prevention of colorectal neoplasia. Critical Reviews in Oncogenesis 1996;7(5&6):293-342.
  113. Giovannucci E, Rimm EB, Stampfer MJ, et al. A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in US men. Journal of the National Cancer Institute 1994;86:183-91.
  114. Giovannucci E, Colditz GA, Stampfer MJ, et al. A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in US women. Journal of the National Cancer Institute 1994;86:192-199.
  115. Heineman EF, Zahm SH, McLaughlin JK, et al. Increased risk of colorectal cancer among smokers: Results of a 26-year follow-up of US veterans and a review. International Journal of Cancer 1995;59:728-738.
  116. Knekt P, Hakama M, Jarvinen R, et al. Smoking and risk of colorectal cancer. British Journal of Cancer 1998;78:136-9.
  117. Nyren O, Bergstrom R, Nystrom L, et al. Smoking and colorectal cancer: a 20-year follow-up sudy of Swedish construction workers. Journal of the National Cancer Institute 1996;88:1302-1307.
  118. Wohlleb JC, Hunter CF, Blass B, et al. Aromatic amine acetyltransferase as a marker for colorectal cancer: environmental and demographic associations. International Journal of Cancer 1990;46:22-30.
  119. Ilett KF, David BM, Detchon P, et al. Acetylation phenotype in colorectal carcinoma. Cancer Research 1987;47:1466-9.
  120. Roberts-Thomson IC, Ryan P, Khoo KK, et al. Diet, acetylator phenotype and risk of colorectal neoplasia. Lancet 1996;347:1372-4.
  121. Lang NP, Butler MA, Massengill J, et al. Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiology, Biomarkers and Prevention 1994;3:675-682.
  122. Oda Y, Tanaka M, Nakanishi I. Relation between the occurrence of K-ras gene point mutations and genotypes of polymorphic N-acetyltransferase in human colorectal carcinomas. Carcinogenesis 1994;15:1365-9.
  123. Jenkins M, Bigler J, Kampman E, et al. Associations between colon cancer and acetylation (NAT1 and NAT2) genotypes in a large population-based study. American Journal of Epidemiology 1997;145:S68.
  124. Probst-Hensch NM, Haile RW, Ingles SA, et al. Acetylation polymorphism and prevalence of colorectal adenomas. Cancer Research 1995;55:2017-20.
  125. Lee E, Huang Y, Zhao B, et al. Genetic polymorphism of conjugating enzymes and cancer risk: GSTM1; GSTT1; NAT1 and NAT2. Journal of Toxicology Sciences 1998;23:140-2.
  126. Kampman E, Slattery ML, Bigler J, et al. Meat consumption, genetic susceptibility, and colon cancer risk: A United States multicenter case-control study. Cancer Epidemiology, Biomarkers and Prevention 1999; 8:15-24.
  127. Bell DA, Badawi AF, Lang NP, et al. Polymorphism in the N-Acetyltransferase 1 (NAT1) Polyadenylation signal: Association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Research 1995;55:5226-9.
  128. Meisel P, Schroeder C, Wulff K, et al. Relationship between human genotype and phenotype of N-acetyltransferase (NAT2) as estimated by discriminant analysis and multiple linear regression: 1. Genotype and N-acetylation in vivo. Pharmacogenetics 1997;7:241-246.
  129. Hanna PE. Metabolic activation and detoxification of arylamines. Current Medicinal Chemistry 1996;3:195-210.
  130. Cotton SC, Sharp L, Little J, et al. Glutathione S Transferase polymorphisms and colorectal cancer: a review. American Journal of Epidemiology (in press).
  131. Crofts F, Taioli E, Trachman J, et al. Functional significance of different human CYP1A1 genotypes. Carcinogenesis 1994;15:2961-3.
  132. Nakajima M, Yokoi T, Mizutani M, et al. Genetic polymorphism in the 5'-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. Journal of Biochemistry 1999;125:803-808.
  133. Sachse C, Brockmöller J, Bauer S, et al. Functional significance of a C®A polymorphism in intron 1 of the cytrochrome P450 CYP1A2 gene tested with caffeine. British Journal of Clinical Pharmacology 1999;47:445-449.
  134. Bigler J, Chen C, Potter JD. Determination of human NAT2 acetylator genotype by oligonucleotide ligation assay. Biotechniques 1997;22:682-4.

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