Detoxification Of Aromatic Amines Research Articles

Assessment of N-acetyltransferase 2 (NAT2) gene polymorphisms in bladder cancer patients

Introduction: Bladder cancer is the most common cancer of the urinary tract. Aromatic amines are incriminated in the pathogenesis of bladder cancer. While many people are exposed to it, only a small proportion of the exposed individuals develop bladder cancer indicating the contribution of genetic variation, namely N-acetyltransferases (NATs) phenotypes (slow and fast acetylator) which are involved in detoxification of aromatic amines and other carcinogenic toxins. Slow acetylators are less efficient in metabolizing aromatic amines, increased toxic burden and subsequently carcinogenesis. Objectives: The aim of this study was to determine whether NAT2 gene polymorphisms (M1, M2 and M3) are associated with bladder cancer formation and with high stage and grade of the tumor. Patients and Methods: This study was conducted on 35 Egyptian bladder cancer patients. Patients further subdivided according to tumor stage and grade. Fifteen patients with benign renal diseases as a pathological control group, in addition to 15 apparently healthy subjects as a healthy control group included in the study. Assay of NAT2 gene single nucleotide polymorphisms (SNPs) was conducted by polymerase chain reaction and restriction fragment length polymorphism (PCRRFLP) technique. Results: Regarding the frequency of NAT2 gene polymorphism, our study revealed that M1 (C481T) mutation was significantly more frequent in patients than controls groups, however no significant differences with M2 or M3 was seen. Conclusion: This investigation implies that NAT2 genotype exhibit no association with the risk of developing bladder cancer, either alone or with smoking. Moreover, there was no association between NAT2 polymorphism and different stages and grades of bladder cancer.

N-acetyltransferase 2 phenotype and risk of esophageal cancer: A meta analysis

N-acetyltransferase 2 (NAT2) gene encodes a phase II enzyme taking part in detoxification of aromatic amines. Published studies have demonstrated that N-Acetyltransferase 2 (NAT2) phenotype is a risk factor of various cancers. Many studies have investigated the association between NAT2 phenotype and susceptibility to esophageal cancer but yielded controversial results. To derive a more precise estimation of this association, a meta-analysis was performed. Electronic databases (Pubmed/Medline, ISI Web of Science and China National Knowledge Infrastructure) in English and Chinese were searched. A total of 5 articles including 476 cases and 1,093 controls were included in this meta-analysis. Odds ratio (OR) with 95% confidence interval (95% CI) was used to evaluate intensity of associations. Pooling studies together, NAT2 slow acetylator phenotype was a significant risk factor of esophageal squamous cell cancer (OR=1.35, 95% CI=1.03-1.77, n=5 studies) but not esophageal adenocarcinoma (OR=0.97, 95% CI=0.47-2.04, n=2 studies). There was a significant association between NAT2 acetylator phenotypes and ESCC in South Asian populations (OR=1.51, 95% CI=1.03-2.20), but not in East Asian populations (OR=1.19, 95% CI=0.80-1.77). Significant association between NAT2 acetylator phenotypes and esophageal cancer was found in population-based control subgroup (OR=1.63, 95% CI=1.07-2.50) but not in hospital-based control subgroup (OR=1.19, 95% CI=0.84-1.69). There is a significant association between NAT2 acetylator phenotype and esophageal cancer in both smokers (OR=1.681, 95% CI=1.179-2.395) and non-smokers (OR=1.614, 95% CI=1.173-2.222). In conclusion, NAT2 slow acetylator phenotype was a significant risk factor of ESCC in Asian populations.

Abstract 1658: Post-GWAS genetic and functional studies for bladder cancer: An uncommon protective synonymous coding variant within the UGT1A6 gene explains the GWAS signal and affects cellular detoxification

Abstract Background: A recent genome-wide association study (GWAS) of bladder cancer identified a single nucleotide polymorphism (SNP), rs11892031, within the UGT1A gene cluster on chromosome 2q37.1, as a novel risk factor. UGT1A locus encodes nine UGT proteins that belong to phase II cellular detoxification system. UGTs are functionally important for detoxification of aromatic amines, which are known risk factors for bladder cancer found in industrial chemicals and tobacco smoke. UGTs are composed of shared exons 2-5 and individual alternative first exons that define enzymatic activity and substrate specificity. Materials and results: We sequenced all nine highly similar alternative first exons of UGT genes in more than 2,000 individuals and identified 27 non-synonymous and 19 synonymous known coding variants, but no novel variants. Imputation based on the GWAS dataset, a combined reference panel of HapMap 3 and 1000 Genomes Projects, and a subset of GWAS samples genotyped for all the identified coding variants, generated data for 1,170 SNPs within the whole UGT region. Of these markers, the strongest association was detected for an uncommon (MAF<0.03) protective genetic variant rs17863783 (OR=0.55, 95%CI=0.44-0.69, p=3.3x10-7 in 4,035 cases and 5, 284 controls; D’=0.96, r2=0.23 with rs11892031). No residual association in this region was detected after adjustment for rs17863783. Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Conclusions: Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease such as bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1658. doi:1538-7445.AM2012-1658

Effect of NAT2 gene polymorphism on bladder cancer risk in Slovak population

N-acetyltransferase 2 (NAT2) is phase II enzyme with major roles in catalyzing the detoxification of aromatic amines, which are known risk factors for bladder cancer, and are ubiquitously present in the environment. We assessed the association between common polymorphisms in NAT2 gene and the risk of bladder cancer in 90 Slovak patients and 274 ethnicity-matched healthy controls. Effect modifications by smoking, age and gender were also evaluated. Overall, NAT2 slow acetylation was associated with significantly increased risk of bladder cancer (OR = 1.90; 95% CI, 1.15-3.16). In stratified analyses by age and gender, the elevated risk conferred by slow acetylator genotype was evident in older individuals (OR = 3.55; 95% CI, 1.77-7.35) and males (OR = 4.65; 95% CI, 1.68-16.10), with further increasing in NAT2*5B/*6A genotype carriers. Smoking was confirmed to be important risk factor, moreover, the risk was markedly increased in smokers with NAT2 slow acetylator genotype, and NAT2*5B/*6A carriers especially. In summary, these findings are consistent with previous literature suggesting that individual susceptibility to bladder cancer may be modulated by NAT2 polymorphisms, particularly in interaction with relevant environmental exposures such as smoking.

Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC) – an investigation in a department of surgical medicine

In the multifactorial aetiology of hepatocellular carcinoma (HCC), an association and interaction between genetic polymorphisms of xenobiotic metabolizing enzymes, lifestyle factors, and cancer risk has been postulated. N-acetyltransferase (NAT2) is involved in the metabolic activation and detoxification of aromatic amines. Aromatic amines are potential hepatocarcinogens in humans. In the present study, we investigated if genetic NAT2 polymorphism is related to HCC. Genotyping of NAT2 was performed in 70 HCC patients and 87 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The results of this investigation show that 46 out 70 HCC patients (65.7%) and 50 out of 87 controls (57.5%) were of the slow acetylator genotypes. The frequency of distribution of slow and rapid acetylators (genotypes) was not significantly different between cases and controls (p > 0.05). Slow acetylator genotypes were not associated with a significantly increased HCC risk (odds ratio, 1.4; 95% confidence interval, 0.74-2.72). A significant association between NAT2 genetic polymorphism and HCC was observed among smokers. Slow acetylator genotypes significantly increased the HCC risk in cigarette smokers (odds ratio, 3.5; 95% confidence interval, 1.38-9.05). Our results suggest that genetic NAT2 polymorphism may play a role in lifestyle factors-related hepatocarcinogenesis. NAT2 activity may be particulary critical in smoking related hepatocarcinogenesis.

Comparison of DNA adduct levels associated with exogenous and endogenous exposures in human pancreas in relation to metabolic genotype

Recently, we examined normal human pancreas tissue for DNA adducts derived from either exogenous chemical exposure and/or endogenous agents. In an effort to explain the different types and levels of DNA adducts formed in the context of individual susceptibility to cancer, we have focused on gene–environment interactions. Here, we report on the levels of hydrophobic aromatic amines (AAs), specifically those derived from 4-aminobiphenyl (ABP), and DNA adducts associated with oxidative stress in human pancreas. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been performed. Using the same DNA, the genotypes were determined for N-acetyltransferase 1 (NAT1), the glutathione S-transferase (GST) M1, GSTP1, GSTT1, and NAD(P)H quinone reductase-1 (NQO 1) as possible modulators of adduct levels because their gene products are involved in the detoxification of AAs, lipid peroxidation products and in redox cycling. These results indicate that ABP–DNA adducts, malondialdehyde–DNA adducts, and 8-oxo-2′-deoxyguanosine (8-oxo-dG) adducts are present at similar levels. Of the metabolic genotypes examined, the presence of ABP–DNA adducts was strongly associated with the putative slow NAT1*4/*4 genotype, suggesting a role for this pathway in ABP detoxification.

Surgical management of periductal mastitis

Although the clinical manifestations of periductal mastitis are now well recognized, the role of cigarette smoking in disease aetiology, and its effect on outcome, are unclear.‘-3 Initial reports that heavy cigarette smoking led to the disease have been verified.2,3 Over 90% of women with mammary duct fistulae, non-lactating breast abscesses and periductal mastitis are heavy cigarette smokersm3 Smoking correlates with the amount of histological periductal inflammatory infiltrate and squamous neoplasia of the terminal lactiferous ducts (leading to duct obstruction) is reported almost exclusively in heavy smokers.’ Altered bacterial population, toxic metabolites (e.g. epoxides), increased tissue damage and microvascular injury have all been suggested as mechanisms by which smoking causes the disease.’ Yet petiductal mastitis is a relatively rare condition, representing only 7% of referrals to a benign breast clinical, even though 33% of women are reported to smoke cigarettes regularly. The recent finding that postmenopausal women with N-acetyl-transferase 2 (NAT2) genetic polymorphisms which leads to slow acetylation and detoxification of carcinogenic aromatic amines in cigarette smoke predisposes women to breast cancer may provide a further clue.” Aromatic amines formed by cigarette smoke are known to cause DNA damage in breast epithelium and induce mammary tumours in laboratory animals. Altered detoxification of aromatic amines caused by inherited genetic polymorphisms, may alter an individual woman’s risk of developing periductal mastitis.6 In this issue of