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World J Hepatol. 2010 March 27; 2(3): 94–102.
Published online 2010 March 27. doi:  10.4254/wjh.v2.i3.94
PMCID: PMC2999273

Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma


In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B1 (AFB1) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB1 exposure and mutations in the K-ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N-acetyltransferases and glutathione S-transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk.

Keywords: Hepatocellular carcinoma, Chemical carcinogens, Aflatoxin B1, Polycyclic aromatic hydrocarbons, 4-aminobiphenyl, Hepatitis B virus, Hepatitis C virus, Glutathione S-transferase, Cytochrome p450 enzymes, Genetic variation


Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies. Worldwide, more than a half million new cases of HCC are reported each year and most patients die within 1 year of diagnosis[1,2]. Although HCC has marked demographic and geographic variations, occurring mainly in East Asia and sub-Saharan Africa[1], it is also increasing in western developed countries such as the United States[3]. Previous studies indicated that hepatocarcinogenesis is a long-term, multistage process with the involvement of multiple risk factors[4]. The major risk factors include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and chemical exposures[5,6]. In specific geographic regions, such as Qidong, China, 40% of HCC can be attributed to exposure to a single chemical carcinogen, aflatoxin B1 (AFB1)[7].

This paper focuses on some representative chemical carcinogens that cause HCC and summarizes advances in our understanding of the correlation between chemical carcinogens and genetic alterations in the development of HCC. There are other exposures which have also been reported to be related with HCC occurrence in animals or for which the correlation between exposure and HCC is not clear. These compounds are not included in this paper.



Aflatoxins are carcinogenic in several animal species but with variable potency[4]. AFB1 is a human hepatocarcinogen and is also a liver carcinogen when fed to certain rodent species[8-10]. It is a secondary metabolite produced by Aspergillus flavus and Aspergillus parasiticus that occurs in tropical and subtropical regions of the world. It contaminates foods such as corn, rice and peanuts that are stored under tropical conditions[11]. Metabolic studies of AFB1 have shown that its active form, AFB1-8, 9-epoxide, is highly mutagenic and carcinogenic for the liver in rats and other experimental animals, with mutagenicity correlating with carcinogenicity[12,13]. AFB1 has also been implicated by epidemiological studies as a causative factor for HCC in humans[14]. The clinical appearance of cancer is the end result of a long chain of cellular and molecular changes and there is substantial evidence that damage to DNA by environmental chemical carcinogens is critical in this process.

AFB1 covalently binds to guanine and cytosine residues of DNA both in vivo and in vitro[15,16] and forms AFB1-DNA adducts; it also forms RNA and protein adducts impairing DNA, RNA and ultimately protein synthesis[17-19]. AFB1-DNA adducts were detected by an immunohistochemical assay in smeared HCC tissues and HCC sections[20-22]. The presence of AFB1-DNA adducts can contribute to genetic alterations in loci involved in the development of HCC. In 1977, Lin et al[23] reported that adduct formation by metabolically activated reactive intermediates with hepatocyte DNA could lead to mutations in the host genome. The p53 tumor suppressor gene is the most frequently mutated gene in human cancers. Two groups found at same time, that mutations of the p53 gene on chromosome 17 are frequent in HCC and a point mutation at the third position of codon 249 resulting in a G:C to T:A transversion was common in HCC tissues which were collected in China and Africa[24,25]. This hotspot mutation in HCC from regions with high levels of dietary aflatoxins links this genetic change to exposure to aflatoxins. Similar results were confirmed in Taiwan HCC samples[22]. Early epidemiologic studies suggested a synergistic effect of AFB1 and HBV infection on HCC risk[26,27] but in our latest study in a larger sample size than both prior studies, the effect was additive[28]. The highly aberrant patterns of genetic changes detected in different areas are suggestive of the genotoxic effects of aflatoxin. The combined effects of HBV and high aflatoxin exposure could promote HCC development[22,29]. In vitro studies exposing human liver cell lines to AFB1 found the same codon 249 mutational pattern on p53[30,31]. In recent years, the p53 codon 249 mutation has also been detected in plasma or serum DNA of HCC patients[32-34]. This mutated DNA may serve as a biomarker of exposure to AFB1 and for detection of early HCC[33].

The molecular mechanisms underlying the carcinogenic effects of AFB1 have also been investigated in rodent models. AFB1-induced HCC in Fischer 344 rats showed activating mutations in codon 12 of K-ras[35], but in human HCC, the incidence of point mutation of K-ras and N-ras oncogenes was low[36]. In an in vitro study, AFB1 interfered with the molecular mechanisms of cell cycle regulation[37]. AFB1 also induced mitotic recombination[38], and minisatellite rearrangements[39]. Mitotic recombination and genetic instability may therefore be alternative mechanisms by which aflatoxin contributes to genetic alterations in HCC[40].

Vinyl chloride (VC)

VC is a major industrial chemical, a wide-spread environmental contaminant and a known animal and human carcinogen[41]. VC is a colorless toxic gas extensively used in the plastic industry. It is absorbed after respiratory exposure and is activated primarily in hepatocytes by the enzyme cytochrome P450 (CYP2E1). Its metabolites can react with DNA bases to form DNA adducts[42]. After metabolic activation, VC induces several DNA adducts and various studies have shown that these DNA adducts are responsible for specific mutations[43]. VC is a multi- potential carcinogen in animals[9,43].

In humans, a causal relationship has been found between occupational exposure to VC and angiosarcoma of the liver[44,45]. In 1983, Evans et al[45] reported two cases of HCC among VC workers. Afterwards, in HCC in workers exposed to VC, a high prevalence of K-ras-2 mutation was reported[46,47]. The p53 mutation pattern in HCC in workers exposed to VC includes point mutations in codons 175, 245, 248, 273 and 282 but it is still unclear whether these genetic changes are directly associated with exposure to VC[48]. However, another study concluded that in humans, A:T base pair mutations in p53 induced by VC represent a specific mutational “signature”[43].

Polycyclic aromatic hydrocarbons (PAHs) and 4-aminobiphenyl (4-ABP)

Cigarette smoking is associated with a significantly increased HCC risk in several epidemiologic studies in Taiwan[49], China[50] and Japan[51]. Chemical carcinogens in tobacco smoke include polycyclic aromatic hydrocarbons such as benzo(a)pyrene [B(a)P], N-nitrosamines and aromatic amines such as 4-aminobiphenyl. PAHs are ubiquitous environmental pollutants produced during all types of combustions of organic materials. Thus, they are found not only in cigarette smoke but also in polluted air, smoked and charbroiled foods, as well as contaminating fats and grains[52]. PAHs, especially B(a)P are known animal and human carcinogens[53]. In male infant mice, exposure to either B(a)P or manufactured gas plant residues which contain known carcinogens, including benzene and PAH, induces liver tumors[54]. In a wild brown bullhead catfish population, a decline in liver neoplasms was observed after a reduction in PAH exposure[55].

In humans, PAH-DNA adducts have been detected in HCC tissue samples[56,57]. Associations with HCC were found for PAH-DNA adducts levels in liver tissues and for the combination of PAH-DNA adducts levels with some susceptibility factors including HBV infection, exposure to AFB1 and other factors[56]. In our study on paraffin tumor tissues and paired plasma samples from HCC patients, we found that the highest PAH-albumin adducts were present in those with the highest mean PAH-DNA adducts in liver, although the results were not statistically significant[57]. A recent study demonstrated that PAH-albumin adducts are associated with increased risk of HCC especially among those with high aflatoxin exposure and that environmental PAH exposure may enhance the hepatic carcinogenic potential of hepatitis B virus infection[56].

4-ABP is a well-studied aromatic amine and a known bladder carcinogen in both experimental animals and humans[58]. It is metabolized by hepatic CYP1A2 to yield N-hydroxyABP, a direct-acting mutagen capable of inducing tumors at sites of application[59]. Animal studies have demonstrated that administration of 4-ABP to dogs results in the formation of N-(deoxyguanonsin-8-yl)-4-ABP (dG-C8-ABP) as the major DNA adduct (approximately 70 percent of total adducts) in hepatocytes and bladder cells[60,61]. In BALB/c mice, there was a linear relationship between levels of dG-C8-ABP in liver DNA and liver tumor incidence[62]. In human liver tissues, higher levels of 4-ABP-DNA were observed in HCC cases compared with controls[63]. Even though there was a dose (number of cigarettes smoked/day)-related increase in 4-ABP DNA and an association with mutant p53 protein expression in bladder cancers[64], so far there are no reports on p53 or other specific gene mutations caused by exposure to PAHs or 4-ABP in HCC.

Arsenic (As)

As is a human carcinogen with various target tissues including liver[65]. Ecological, case-control and cohort studies have documented a significant association between HCC and ingested inorganic arsenic through medicinal, environmental and occupational exposures in Taiwan and other countries[66]. A recent study indicated that fetal exposure to inorganic arsenic in mice produces tumors in adulthood in a variety of organs, including liver[67]. Several potential mechanisms for arsenical-induced hepatocarcinogenesis have been proposed including oxidative DNA damage, impaired DNA repair, acquired apoptotic tolerance, hyperproliferation, altered DNA methylation and aberrant estrogen signaling[68]. A marked overexpression of hepatic ER-α at the transcript and protein levels occurred in adult males bearing HCC induced by in utero arsenic exposure[69]. Increases in hepatic cyclin D1 expression, an ER activated hepatic oncogene, also occurred[70].


Ethanol is a hepatotoxin and the most prevalent cause of cirrhosis, a primary clinical predictor of HCC, in western countries. Additionally, alcohol is an important solvent for chemicals and promotes the absorption of ingested toxins[71]. Ethanol damages the liver through oxidative-stress mechanisms; alcoholic hepatitis shows increased levels of isoprostanes, a marker of oxidative damage[72]. Oxidative stress can also cause the accumulation of oncogenic mutations. For example, increased oxidative stress associated with iron overload has been associated with p53 mutations in HCC[73]. Oxidative damage may also accelerate telomere shortening which is correlated with the development of liver cirrhosis, chromosomal instability and HCC[74].


Most chemical carcinogens are not intrinsically reactive. They require metabolic conversion into biologically active forms by phase I enzymes, including various CYP enzymes. Activated metabolites of chemical carcinogens are subject to metabolic conjugation and other kinds of detoxification by phase II enzymes including epoxide hydrolase, arylamine N-acetyltransferases (NAT) and glutathione S-transferases (GST). Studies have demonstrated gene-environment interactions in which risk of HCC from exposure to environmental agents was modulated by genetic susceptibility related to genetic variations in chemical carcinogen metabolism genes.


The CYP enzymes are a superfamily of hemeproteins that are important in the oxidative, peroxidative and reductive metabolism of endogenous compounds and participate in the chemical carcinogenesis process[75]. Aflatoxin is activated by CYP1A2 and CYP3A4 to AFB1-8, 9-epoxide, which covalently binds with DNA to form DNA-adducts, primarily AFB1-N7-guanine[76,77]. CYP2A6 and CYP2B6 likely represent minor forms in the in vitro activation of AFB1[78]. The overall contribution of these enzymes to AFB1 metabolisms in vitro depends on the affinity of the enzyme but in vivo it also depends on expression levels in human liver where CYP3A4 is predominant[40]. Expression of CYP1A1/2 and 3A4 in liver tissues of hepatocellular carcinoma cases and controls was detected and their relationship to HBV and AFB1- and 4-ABP-DNA adducts was also investigated[79]. For CYP3A4, in contrast to control tissues, there was a significant association with AFB1-DNA adducts in tumor and adjacent non-tumor tissues of HCC cases.

Humans show large interindividual variations in xenobiotic metabolism activities that lead to different susceptibilities to the genotoxic actions of carcinogens[80]. A model using human liver epithelial cell lines stably expressing P450 cDNA revealed that CYP1A2 and CYP3A4 both contribute to the formation of AFB1-induced p53 mutation whereas CYP2A6 does not appear to play a significant role[31]. In an in vitro study, inhibition of CYP1A2 and CYP3A4 by oltipraz, a drug which has been reported to inhibit AFB1 activation in human hepatocytes, was shown[81].

GST are a family of conjugation enzymes involved in the metabolism of exogenous and endogenous lipophilic compounds for their excretion and detoxification. For AFB1, the detoxification pathway is via GST-mediated conjugation with reduced glutathione (GSH) to form AFB1 exo- and endo-epoxide GSH conjugates[76,82,83]. Members of the GST family, such as GST-μ (GSTM1) and GST-θ (GSTT1), are important candidates for involvement in susceptibility to AFB-associated HCC because they may regulate an individual’s ability to metabolize the ultimate carcinogen of aflatoxin, the exo-epoxide[83]. Epidemiological studies have suggested that genetic polymorphisms in AFB1 metabolizing enzymes are factors in individual susceptibility to aflatoxin-related HCC[84,85]. GSTM1 genotype can be categorized into two classes: the homozygous deletion genotype (GSTM1 null genotype) and genotypes with one or two alleles present (GSTM1 non-null genotype); GSTT1 can also be deleted[86,87]. Carriers of GSTM1 and GSTT1 homozygous null genotypes lack the corresponding enzyme activities[86]. Chen et al[85] documented a biological gradient between serum AFB1-albumin adduct levels and HCC risk among chronic HBsAg carriers who had null GSTM1 and GSTT1 genotypes but not among those who had non-null genotypes in a Taiwan population. Wild et al[88] reported in a Gambian population an association between the GSTM1 null genotype and AFB1-albumin adducts, although the association was restricted to people who were not infected with HBV. The effect of aflatoxin exposure on HCC risk was also more pronounced among chronic HBsAg carriers with the GSTT1 null genotype than those who were non-null[89]. Based on the above studies conducted in different places and others not reviewed, whether or not there are interactions among AFB1, HBV infection and GSTs genotypes in the development of HCC is still controversial.


Vinyl chloride is primarily metabolized in the liver by the CYP2E1 to form the electrophilic metabolites chloroethylene oxide and chloroacetaldehyde[90]. These metabolites are thought to be the reactive intermediates involved in the formation of VC-DNA adducts. The promutagenic properties of these adducts have been characterized extensively in vivo and in vitro and involve mainly base pair substitution mutations[91]. Metabolism of the reactive intermediates is thought to involve several pathways that rely on CYP2E1, aldehyde dehydrogenase 2, GSTs, microsomal epoxide hydrolase and other enzymes, presumably to generate less reactive metabolites for excretion[92]. All of those enzymes are known to have polymorphic variants with altered activities that could produce variable VC metabolism[93]. Such variable metabolism could account for differing susceptibilities to the carcinogenic effects of VC in exposed individuals. The GST family is known to be involved in the metabolism of environmental chemical carcinogens including vinyl chloride monomer; it plays critical roles in protection against products of oxidative stress and electrophilic compounds[94,95]. So far, no direct evidence has shown that genetic polymorphisms of metabolizing enzymes are correlated with HCC development caused by VC exposure.

PAH and 4-ABP

CYP1A1 metabolically activates PAH into carcinogenic metabolites (diol epoxides), which covalently bind to DNA to form DNA-adducts[96], while CYP1A2 metabolically activates arylamine carcinogens such as 4-ABP and heterocyclic amines derived from cooked meats[90]. CYP1A1 was generally considered to be involved in extra hepatic carcinogenesis because early studies showed that the expression of CYP1A1 was low in human liver[90]. A later study using more sensitive techniques for the detection of CYP1A1 messenger RNA demonstrated that CYP1A1 is expressed in a high proportion of human liver tissues[97]. A study of the role of CYP1A1 genetic polymorphism in susceptibility to HCC has suggested that CYP1A1 variants are important modulators of the hepatocarcinogenic effect of PAHs. The Msp1 and lle-Val polymorphisms of CYP1A1 may have different mechanisms for increasing susceptibility to smoking-related HCC[98]. Recently, a second study obtained similar result but in non-smoking HCC patients[99]. These inconsistent findings justify the need for additional studies of larger sample sizes to further evaluate the role of the CYP1A1 variants in HCC development. Chen et al[100] reported genetic polymorphism of CYP1A2 is associated with HCC risk. Polymorphisms of CYP2E1 may also play an important role in cigarette smoking-related hepatocarcinogenesis[101].

Activated metabolites of B(a)P are subject in part to metabolic detoxification by GSTM1[102]; GSTT1 can detoxify smaller reactive hydrocarbons[103]. Diol epoxides are substrates for phase II detoxifying enzymes including GSTP1[104]. Alterations in the expression of GSTs have been found in HCC tissues compared to liver tissues from healthy subjects[105]. These alterations may influence the association between exposure and PAH-DNA adduct formation among HCC cases. Chen et al[56] reported a significant combinatory effect of PAH-DNA adduct levels and GSTP1 genotype on HCC risk but in the same study there were no associations between HCC and GSTM1 or GSTP1 genotype. Subjects with high compared to low PAH-DNA adduct levels had a 2-fold higher HCC risk after adjustment either for age, sex and HBsAg or for age, sex, HBsAg, 4-ABP- and AFB1-DNA adduct levels. Evidence of a possible interaction between GST polymorphisms and smoking was reported in two studies[106,107], with a non significant excess risk reported among light smokers with the GSTT1 null genotype in one study[107] and a significant excess risk among smokers with a GSTM1 and GSTT1 null genotypes and low levels of plasma beta-carotene reported in the other[106].

NAT plays a role in the activation and detoxification of certain carcinogens in tobacco smoke[108]. Two isoforms of NAT1 and NAT2 participate in the metabolic activation and detoxification (O- and N-acetylation respectively) of aromatic amines (including arylamines and heterocyclic amines)[108], which are found in tobacco smoke. Exposure to 4-ABP, which is primarily a result of cigarette smoking, plays a role in human hepatocarcinogenesis[63]. Wang et al[63] found greater levels of 4-ABP-DNA in liver tissues from HCC patients than controls. NAT1 and especially NAT2 are characterized by several allelic variants, which cause variations in acetylation capacity. Agundez et al[109] investigated the effect of NAT2 polymorphisms on HCC and found they are relevant to HCC risk. Results of a study in Taiwan suggested that NAT2 activity may be particularly critical in smoking-related hepatocarcinogenesis among chronic HBV carriers[110]. Farker et al[111] reported a significant association between NAT2 polymorphism and HCC among chronic HBV carriers who were smokers but not among those who were non-smokers. It was postulated that genetic polymorphisms in biotransformation enzymes could be important with regards to individual susceptibility to cigarette smoking-related HCC[109,112].


Inorganic arsenic (iAs) is metabolized by reduction of pentavalent iAs to trivalent, followed by oxidative methylation to monomethylated arsenic (MMA), further reduction from pentavalent MMA to trivalent, and finally methylation to dimethyl arsenic[113]. One study indicated that polymorphisms in GST omega 1, which encodes an enzyme that can reduce pentavalent arsenic species, might be related to enzyme activity and patterns of methylated arsenic metabolites[114,115]. Because glutathione plays an important role in arsenic metabolism, its regulation via GST polymorphisms may modulate metabolism and, as a consequence, alter urinary excretion profiles. Thus, as low GST activity may decrease the detoxification function of glutathione, it has been hypothesized that humans with null genotypes for GSTM1 and GSTT1 may have arsenic methylation capabilities and body retention differences compared to those with non-null genotypes. In addition, humans with null genotypes for GSTM1 and GSTT1, as well as the val/val genotype for GSTP1, may be at high risk of cancer due to their glutathione deficiencies[116].


Alcohol consumption also induces the expression of a number of xenobiotic metabolism enzymes that activate procarcinogens[4]. CYP2E1, one of the important members of the CYP super family, catalyses the conversion of ethanol to acetaldehyde and acetate but also metabolizes many exogenous drugs and procarcinogens[116]. As CYP2E1 is an ethanol inducible enzyme, its functional characterization has been focused on alcoholic liver diseases[117]. Decreased expression of CYP2E1 is associated with poor prognosis of hepatocellular carcinoma[118].


Exposure to chemical carcinogens including AFB1, B(a)P, 4-ABP, arsenic, alcohol and others may act either independently or interact with HBV and HCV to cause DNA damage, induce liver cirrhosis and contribute to the development of HCC. During this process, genetic variation will impact on risk. Various types of genotoxic endpoints including DNA-adducts, point mutations of tumor suppressor genes and other cancer-related genes, small deletions (loss of heterozygosity) and chromosomal aberrations are dominant characteristics of HCC.

Metabolism of chemical carcinogens involves multiple pathways of transformation of certain chemicals. Thus, the regulation of genes coding for many of these metabolic enzymes is important in hepatocarcinogenesis and has lead to studies of inter-individual genetic variation.

Understanding the interaction of viral infection, genetic variation and exposure to environmental chemical carcinogens will help to elucidate mechanisms of human hepatocarcinogenesis and develop more effective strategies for HCC prevention.


The author is grateful to Dr. Regina M Santella for providing valuable comments.


Supported by NIH grants ES005116 and ES009089

Peer reviewer: Isabel Fabregat Romero, PhD, Laboratori de Oncologia Molecular, Institut de Investigació Biomèdica de Bellvitge, Gran via de Hospitalet, Barcelona 08907, Spain

S- Editor Wang JL L- Editor Roemmele A E- Editor Liu N


1. Schafer DF. and Sorrell MF. Hepatocellular carcinoma. Lancet. 1999;353:1253–1257. [PubMed]
2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. [PubMed]
3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750. [PubMed]
4. Chen CJ, Chen DS. Interaction of hepatitis B virus, chemical carcinogen, and genetic susceptibility: multistage hepatocarcinogenesis with multifactorial etiology. Hepatology. 2002;36:1046–1049. [PubMed]
5. Wang XW, Hussain SP, Huo TI, Wu CG, Forgues M, Hofseth LJ, Brechot C, Harris CC. Molecular pathogenesis of human hepatocellular carcinoma. Toxicology. 2002;181-182:43–47. [PubMed]
6. Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26:2166–2176. [PubMed]
7. Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC, Wang N, Shao Y, Wu Z, Liu G, Wang X, et al. Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology. 2002;36:1214–1220. [PubMed]
8. Wogan GN, Newberne PM. Dose-response characteristics of aflatoxin B1 carcinogenesis in the rat. Cancer Res. 1967;27:2370–2376. [PubMed]
9. Wogan GN. IARC. Monographs on the evaluation of carcinogenic risk to humans. Lyon, France: IARC Publications; 1987.
10. Wogan GN. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res. 1992;52:2114s–2118s. [PubMed]
11. Wogan GN. Aflatoxins and their relationship to hepatocellular carcinoma. In: Okuda K and Peters RL., editor. Hepatocellular Carcinoma. New York: John Wiley and Sons; 1976. pp. 25–42.
12. Newberne PM, Wogan GN. Sequential morphologic changes in aflatoxin B carcinogenesis in the rat. Cancer Res. 1968;28:770–781. [PubMed]
13. Swenson DH, Miller EC, and Miller JA. Aflatoxin B1-2,3-oxide: evidence for its formation in rat liver in vivo and by human liver microsomes in vitro. Biochem Biophys Res Commun. 1974;60:1036–1043. [PubMed]
14. Ross RK, Yuan JM, Yu MC, Wogan GN, Qian GS, Tu JT, Groopman JD, Gao YT, and Henderson BE Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet. 1992;339:943–946. [PubMed]
15. Croy RG, Essigmann JM, Reinhold VN, and Wogan GN. Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver. Proc Natl Acad Sci USA. 1978;75:1745–1749. [PubMed]
16. Yu FL, Bender W, Hutchcroft A. Studies on the binding and transcriptional properties of aflatoxin B1-8,9-epoxide. Carcinogenesis. 1994;15:1737–1741. [PubMed]
17. Santella RM, Chen CJ, Zhang YJ, Yu MW, and Wang LY. Biological markers of aflatoxin B1 in hepatocellular cancer in Taiwan. In: Mendelsohn ML, Mohr LC and Peeters JP, editors. Biomarkers medical and workplace applications. Washington, DC: Joseph Henry Press; 1998. pp. 355–364.
18. Meneghini R, Schumacher RI. Aflatoxin B1, a selective inhibitor of DNA synthesis in mammalian cells. Chem Biol Interact. 1977;18:267–276. [PubMed]
19. Amstad P, Cerutti P. DNA binding of aflatoxin B1 by co-oxygenation in mouse embryo fibroblasts C3H/10T1/2. Biochem Biophys Res Commun. 1983;112:1034–1040. [PubMed]
20. Chen CJ, Zhang YJ, Lu SN, Santella RM. Aflatoxin B1 DNA adducts in smeared tumor tissue from patients with hepatocellular carcinoma. Hepatology. 1992;16:1150–1155. [PubMed]
21. Zhang YJ, Chen CJ, Lee CS, Haghighi B, Yang GY, Wang LW, Feitelson M, Santella R. Aflatoxin B1-DNA adducts and hepatitis B virus antigens in hepatocellular carcinoma and non-tumorous liver tissue. Carcinogenesis. 1991;12:2247–2252. [PubMed]
22. Lunn RM, Zhang YJ, Wang LY, Chen CJ, Lee PH, Lee CS, Tsai WY, Santella RM. p53 mutations, chronic hepatitis B virus infection, and aflatoxin exposure in hepatocellular carcinoma in Taiwan. Cancer Res. 1997;57:3471–3477. [PubMed]
23. Lin JK, Miller JA, Miller EC. 2,3-Dihydro-2-(guan-7-yl)-3-hydroxy-aflatoxin B1, a major acid hydrolysis product of aflatoxin B1-DNA or -ribosomal RNA adducts formed in hepatic microsome-mediated reactions and in rat liver in vivo. Cancer Res. 1977;37:4430–4438. [PubMed]
24. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350:427–428. [PubMed]
25. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991;350:429–431. [PubMed]
26. Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev. 1994;3:3–10. [PubMed]
27. Wang LY, Hatch M, Chen CJ, Levin B, You SL, Lu SN, Wu MH, Wu WP, Wang LW, Wang Q, et al. Aflatoxin exposure and the risk of hepatocellular carcinoma in Taiwan. Int J Cancer. 1996;67:620–625. [PubMed]
28. Wu HC, Wang Q, Wang LW, Yang HI, Ahsan H, Tsai WY, Wang LY, Chen SY, Chen CJ, Santella RM. Urinary 8-oxodeoxyguanosine, aflatoxin B1 exposure and hepatitis B virus infection and hepatocellular carcinoma in Taiwan. Carcinogenesis. 2007;28:995–999. [PubMed]
29. Wong N, Lai P, Pang E, Fung LF, Sheng Z, Wong V, Wang W, Hayashi Y, Perlman E, Yuna S, et al. Genomic aberrations in human hepatocellular carcinomas of differing etiologies. Clin Cancer Res. 2000;6:4000–4009. [PubMed]
30. Aguilar F, Hussain P, and Cerutti P. Aflatoxin B1 induces the transversion of G- T in codon 249 of the p53 tumor suppressor gene in human hepatyocytes. Proc Natl Acad Sci USA. 1993;90:8586–8590. [PubMed]
31. Macé K, Aguilar F, Wang JS, Vautravers P, Gómez-Lechón M, Gonzalez FJ, Groopman J, Harris CC, Pfeifer AM. Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis. 1997;18:1291–1297. [PubMed]
32. Kirk GD, Camus-Randon AM, Mendy M, Goedert JJ, Merle P, Trépo C, Bréchot C, Hainaut P, Montesano R. Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia. J Natl Cancer Inst. 2000;92:148–153. [PubMed]
33. Jackson PE, Qian GS, Friesen MD, Zhu YR, Lu P, Wang JB, Wu Y, Kensler TW, Vogelstein B, Groopman JD. Specific p53 mutations detected in plasma and tumors of hepatocellular carcinoma patients by electrospray ionization mass spectrometry. Cancer Res. 2001;61:33–55. [PubMed]
34. Kuang SY, Lekawanvijit S, Maneekarn N, Thongsawat S, Brodovicz K, Nelson K, Groopman JD. Hepatitis B 1762T/1764A mutations, hepatitis C infection, and codon 249 p53 mutations in hepatocellular carcinomas from Thailand. Cancer Epidemiol Biomarkers Prev. 2005;14:380–384. [PubMed]
35. McMaho G, Davis EF, Huber LJ, Kim Y, and Wogan GN. Characterization of c-Ki-ras and N-ras oncogenes in aflatoxin B1-induced rat liver tumors. Proc Natl Acad Sci USA. 1990;87:1104–1108. [PubMed]
36. Tsuda H, Hirohashi S, Shimosato Y, Ino Y, Yoshida T, Terada M. Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn J Cancer Res. 1989;80:196–199. [PubMed]
37. Ricordy R, Gensabella G, Cacci E, Augusti-Tocco G. Imp–airment of cell cycle progression by aflatoxin B1 in human cell lines. Mutagenesis. 2002;17:241–249. [PubMed]
38. Stettler PM, Sengstag C. Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell line. Mol Carcinog. 2001;31:125–138. [PubMed]
39. Kaplanski C, Chisari FV, Wild CP. Minisatellite rearrangements are increased in liver tumours induced by transplacental aflatoxin B1 treatment of hepatitis B virus transgenic mice, but not in spontaneously arising tumours. Carcinogenesis. 1997;18:633–639. [PubMed]
40. Wild CP, Turner PC. The toxicology of aflatoxins as a basis for public health decisions. Mutagenesis. 2002;17:471–481. [PubMed]
41. Wild CP. IARC. Vinyl chloride IARC Monograph on evolution of carcinogenic risk of chemicals to humans. Washington DC: US Govt; 1974.
42. Guengerich FP. Roles of the vinyl chloride oxidation products 1-chlorooxirane and 2-chloroacetaldehyde in the in vitro formation of etheno adducts of nucleic acid bases [corrected] Chem Res Toxicol. 1992;5:2–5. [PubMed]
43. Barbin A, Froment O, Boivin S, Marion MJ, Belpoggi F, Maltoni C, Montesano R. p53 gene mutation pattern in rat liver tumors induced by vinyl chloride. Cancer Res. 1997;57:1695–1698. [PubMed]
44. Tamburro CH, Makk L, Popper H. Early hepatic histologic alterations among chemical (vinyl monomer) workers. Hepatology. 1984;4:413–418. [PubMed]
45. Evans DM, Williams WJ, Kung IT. Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology. 1983;7:377–388. [PubMed]
46. Weihrauch M, Benick M, Lehner G, Wittekind M, Bader M, Wrbitzk R, Tannapfel A. High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride. I. nt Arch Occup Environ Health. 2001;74:405–410. [PubMed]
47. Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k- ras -2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in wokers exposed to vinyl chloride. Br J Cancer. 2001;84:982–989. [PMC free article] [PubMed]
48. Weihrauch M, Lehnert G, Kockerling F, Wittekind C, and Tannapfel A. p53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride. Cancer. 2000;88:1030–1036. [PubMed]
49. Chen CJ, Wang LY, Lu SN, Wu MH, You SL, Zhang YJ, Wang LW, Santella RM. Elevated aflatoxin exposure and increased risk of hepatocellular carcinoma. Hepatology. 1996;24:38–42. [PubMed]
50. Tu JT, Gao RN, Zhang DH, Gu BC. Hepatitis B virus and primary liver cancer on Chongming Island, People’s Republic of China. Natl Cancer Inst Monogr. 1985;69:213–215. [PubMed]
51. Goodman MT, Moriwaki H, Vaeth M, Akiba S, Hayabuchi H, Mabuchi K. Prospective cohort study of risk factors for primary liver cancer in Hiroshima and Nagasaki, Japan. Epidemiology. 1995;6:36–41. [PubMed]
52. Phillips DH. Polycyclic aromatic hydrocarbons in the diet. Mutat Res. 1999;443:139–147. [PubMed]
53. IARC Polynuclear Aromatic Compounds, Part 1. Chemical Environmental nd Experimental Data. IARC Monographs on the Evaluation ofthe Carcinogenic Risk of Chemicals to Humans. International Agency for Research on Cancer. Washington DC: US Govt; 1983. pp. 1–453.
54. Rodriguez LV, Dunsford HA, Steinberg M, Chaloupka KK, Zhu L, Safe S, Womack JE, Goldstein LS. Carcinogenicity of benzo[a]pyrene and manufactured gas plant residues in infant mice. Carcinogenesis. 1997;18:127–135. [PubMed]
55. Baumann PC, Harshbarger JC. Decline in liver neoplasms in wild brown bullhead catfish after coking plant closes and environmental PAHs plummet. Environ Health Perspect. 1995;103:168–170. [PMC free article] [PubMed]
56. Chen SY, Wang LY, Lunn RM, Tsai WY, Lee PH, Lee CS, Ahsan H, Zhang YJ, Chen CJ, Santella RM. Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls. Int J Cancer. 2002;99:14–21. [PubMed]
57. Zhang YJ, Rossner P Jr, Chen Y, Agrawal M, Wang Q, Wang L, Ahsan H, Yu MW, Lee PH, Santella RM. Aflatoxin B1 and polycyclic aromatic hydrocarbon adducts, p53 mutations and p16 methylation in liver tissue and plasma of hepatocellular carcinoma patients. Int J Cancer. 2006;119:985–991. [PubMed]
58. Bartsch H, Malaveille C, Friesen M, Kadlubar FF, and Vineis P. Black (air-cured) and blond (flue-cured) tobacco cancer risk. IV: Molecular dosimetry studies implicate aromatic amines as bladder carcinogens. Eur J Cancer. 1993;29:1199–1207. [PubMed]
59. Butler MA, Iwasaki M, Guengerich FP, and Kadlubar, FF Human cytochrome P-450A (P-4501A2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci USA. 1989;86:7696–7700. [PubMed]
60. Talaska G, Dooley KL, Kadlubar FF. Detection and characterization of carcinogen-DNA adducts in exfoliated urothelial cells from 4-aminobiphenyl-treated dogs by 32P-postlabelling and subsequent thin-layer and high-pressure liquid chromatography. Carcinogenesis. 1990;11:639–646. [PubMed]
61. Kadlubar FF. DNA adducts of carcinogenic aromatic amines. In: Hemminki KDASDE, editor. DNA adducts identification and biological significance (IARC Scientific Publication No.125) New York: Oxford University Press; 1994. pp. 199–215.
62. Poirier MC, Fullerton NF, Smith BA, Beland FA. DNA adduct formation and tumorigenesis in mice during the chronic administration of 4-aminobiphenyl at multiple dose levels. Carcinogenesis. 1995;16:2917–2921. [PubMed]
63. Wang LY, Chen CJ, Zhang YJ, Tsai WY, Lee PH, Feitelson MA, Lee CS, Santella RM. 4-Aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls. Am J Epidemiol. 1998;147:315–323. [PubMed]
64. Curigliano G, Zhang YJ, Wang LY, Flamini G, Alcini A, Ratto C, Giustacchini M, Alcini E, Cittadini A, Santella RM. Immunohistochemical quantitation of 4-aminobiphenyl-DNA adducts and p53 nuclear overexpression in T1 bladder cancer of smokers and nonsmokers. Carcinogenesis. 1996;17:911–916. [PubMed]
65. Curigliano G. IARC. IARC Monographys on evaluation of carcinogenic risk to humans. In Some Drinking Water Disinfectants and Contaminants, including Arsenic. International Agency for Research on Cancer. IARC Monogr Eval Carcinog Risks Hum. 2004;84:296–477.
66. Chen CJ, Lin L. Carcinigenicity and atherogenicity induced by chronic exposure to inorganic arsenic. In: Nriagu O, editor. Arsenic in the Environment. New York: John Wiley & Sons Inc; 1994. pp. 109–131.
67. Waalkes MP, Liu J, Diwan BA. Transplacental arsenic carcinogenesis in mice. Toxicol Appl Pharmacol. 2007;222:271–280. [PMC free article] [PubMed]
68. Liu J, Waalkes MP. Liver is a target of arsenic carcinogenesis. Toxicol Sci. 2008;105:24–32. [PMC free article] [PubMed]
69. Waalkes MP, Ward JM, Diwan BA. Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis. 2004;25:133–141. [PubMed]
70. Deane NG, Parker MA, Aramandla R, Diehl L, Lee WJ, Washington MK, Nanney LB, Shyr Y, Beauchamp RD. Hepatocellular carcinoma results from chronic cyclin D1 overexpression in transgenic mice. Cancer Res. 2001;61:5389–5395. [PubMed]
71. Chen CJ, Yu MW, Liaw YF. Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12:S294–S308. [PubMed]
72. McClain CJ, Hill DB, Song Z, Chawla R, Watson WH, Chen T, and Barve, S S-Adenosylmethionine, cytokines, and alcoholic liver disease. Alcohol. 2002;27:185–192. [PubMed]
73. Marrogi AJ, Khan MA, van Gijssel HE, Welsh JA, Rahim H, Demetris AJ, Kowdley KV, Hussain SP, Nair J, Bartsch H, et al. Oxidative stress and p53 mutations in the carcinogenesis of iron overload-associated hepatocellular carcinoma. J Natl Cancer Inst. 2001;93:1652–1655. [PubMed]
74. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci. 2004;117:2417–2426. [PubMed]
75. Gonzalez FJ, Lee YH. Constitutive expression of hepatic cytochrome P450 genes. FASEB J. 1996;10:1112–1117. [PubMed]
76. Guengerich FP, Johnson WW, Shimada T, Ueng YF, Yamazaki H, and Langouet S. Activation and detoxification of aflatoxin B1. Mutat Res. 1998;402:121–128. [PubMed]
77. Iyer R, Voehler M, and Harris TM. Adenine adduct of aflatoxin B1 epoxide. J Am Chem Soc. 1994;116:8863–8869.
78. Pfeifer AM, Cole KE, Smoot DT, Weston A, Groopman JD, Shields PG, Vignaud JM, Juillerat M, Lipsky MM, Trump BF. Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. Proc Natl Acad Sci USA. 1993;90:5123–5127. [PubMed]
79. Zhang YJ, Chen SY, Tsai WY, Ahsan H, Lunn R, Wang LY, Chen CJ, and Santella RM. Expression of cytochrome P450 1A1/2 and 3A4 in liver tissues of hepatocellular carcinoma cases and controls from Taiwan and their relationship to hepatitis B virus and aflatoxin B1- and 4-aminobiphenyl-DNA adducts. Biomarkers. 2000 [PubMed]
80. Harris CC. Interindividual variation among humans in carcinogen metabolism, DNA adduct formation and DNA repair. Carcinogenesis. 1989;10:1563–1566. [PubMed]
81. Langouët S, Coles B, Morel F, Becquemont L, Beaune P, Guengerich FP, Ketterer B, Guillouzo A. Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture. Cancer Res. 1995;55:5574–5579. [PubMed]
82. Raney KD, Meyer DJ, Ketterer B, Harris TM, and Guengerich FP. Glutathione conjugation of aflatoxin B1 exo- and endo-epoxide by rat and human glutathione S-transferases. Chem Res Toxicol. 1992;5:470–478. [PubMed]
83. Johnson WW, Ueng YF, Widersten M, Mannervik B, Hayes JD, Sherratt PJ, Ketterer B, and Guengerich FP. Conjugation of highly reactive aflatoxin B1 exo-8,9-epoxide catalyzed by rat and human glutathione transferases: estimation of kinetic parameters. Biochemistry. 1997;36:3056–3060. [PubMed]
84. McGlynn KA, Rosvold EA, Lustbader ED, Hu Y, Clapper M. Zhou T, Wild CP, Xia XL, Baffoe-Bonnie,A, Ofori-Adjei D, Chen GC, London WT, Shen FJ, and Buetow KH. Susceptibility to hepatocellular carcinoma is associated with gentic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci USA. 1995;92:2384–2387. [PubMed]
85. Chen CJ, Yu MW, Liaw YF, Wang LW, Chiamprasert S, Matin F, Hirvonen A, Bell DA, and Santella RM. Chronic hepatitis B carriers with null genotypes of gluthione S-transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma. Am J Hum Genet. 1996;59:128–134. [PubMed]
86. Pemble S, Schiroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, and Taylor JB. Human glutathione S-transferase theta (GSTT1) cDNA cloning and the characterization of a genetic polymorphism. Biochem. 1994;300:271–276. [PubMed]
87. Rebbeck TR, Walker AH, Jaffe JM, White DL, Wein AJ, and Malkowicz SB. Glutathione S-transferase-mu (GSTM1) and -theta (GSTT1) genotypes in the etiology of prostate cancer. Cancer Epidemiol Biomarkers Prev. 1999;8:283–287. [PubMed]
88. Wild CP, Yin F, Turner PC, Chemin I, Chapot B, Mendy M, Whittle H, Kirk GD, and Hall AJ. Environmental and genetic determinants of aflatoxin-albumin adducts in the Gambia. Int J Cancer. 2000;86:1–7. [PubMed]
89. Sun CA, Wang LY, Chen CJ, Lu SN, You SL, Wang LW, Wang Q, Wu DM and Santella RM. Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. Carcinogenesis. 2001;22:1289–1294. [PubMed]
90. Guengerich FP, Kim DH, and Iwasaki M. Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991;4:168–179. [PubMed]
91. Grollman A, Shibutani S. Mutagenic specificity of chemical carcinogens as determined by studies of single DNA adducts. In: IARC , editor. DNA Adducts: Identification and Biological Significance. Lyon: Scientific Publ; 1994. pp. 385–397. [PubMed]
92. Agency for toxic substances and disease registry toxilogical profile for vinyl chloride. In US Department of Health and Human Services, editor. Atlanta. Lyon: Scientific Publ; 1997.
93. Vineis P. Individual susceptibility to carcinogens. Oncogene. 2004;23:6477–6483. [PubMed]
94. Ketterer B. Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat Res. 1988;202:343–361. [PubMed]
95. Autrup H. Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response. Mutat Res. 2000;464:65–76. [PubMed]
96. Shimada T, Yun CH, Yamazaki H, Gautier JC, Beaune PH, and Guengerich FP. Characterization of human lung microsomal cytochrome P450 1A1 and its role in the oxidation of chemical carcinogens. Mol Pharm. 1992;41:856–864. [PubMed]
97. Schweikl H, Taylor JA, Kitareewan S, Linko P, Nagorney D, and Goldstein JA. Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics. 1993;3:239–249. [PubMed]
98. Yu MW, Chiu YH, Yang SY, Santella RM, Chern HD, Liaw YF, and Chen CJ. Cytochrome P450 1A1 genetic polymorphisms and risk of hepatocellular carcinoma among chronic hepatitis B carriers. Brit J Cancer. 1999;80:598–603. [PMC free article] [PubMed]
99. Li R, Shugart YY, Zhou W, An Y, Yang Y, Zhou Y, Zhang B, Lu D, Wang H, Qian J, et al. Common genetic variations of the cytochrome P450 1A1 gene and risk of hepatocellular carcinoma in a Chinese population. Eur J Cancer. 2009;45:1239–1247. [PubMed]
100. Chen X, Wang H, Xie W, Liang R, Wei Z, Zhi L, Zhang X, Hao B, Zhong S, Zhou G, et al. Association of CYP1A2 genetic polymorphisms with hepatocellular carcinoma susceptibility: a case-control study in a high-risk region of China. Pharmacogenet Genomics. 2006;16:219–227. [PubMed]
101. Lam KC, Yu MC, Leung JWC and Henderson BE. Hepatitis B virus and cigarette smoking: risk factors for hepatocellural carcinoma in Hong Kong. Cancer Res. 1982;42:5246–5248. [PubMed]
102. Mannervik B, Danielson UH. Glutathione transferases--structure and catalytic activity. CRC Crit RevBiochem. 1988;23:283–337. [PubMed]
103. Daniel V. Glutathione S-transferases: gene structure and regulation of expression. Crit Rev Biochem Mol Biol. 1993;28:173–207. [PubMed]
104. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30:445–600. [PubMed]
105. Zhou T, Evans AA, London WT, Xia X, Zou H, Shen F, and Clapper ML. Glutathione S-transferase expression in hepatitis B virus-associated human hepatocellular carcinogenesis. Cancer Res. 1997;57:2749–2753. [PubMed]
106. Yu MW, Chiu YH, Chiang YC, Chen CH, Lee TH, Santella RM. Chern HD, Liaw YF, and Chen CJ. Plasma carotenoids, glutatione S-transferase M1 and T1 genetic polymorphisms, and risk of hepatocellular carcinoma: independent and interactive effects. Am J Epidemiol. 1999;149:621–629. [PubMed]
107. Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, Oda S, and Katoh T. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol. 2003;129:355–360. [PubMed]
108. Hein DW, Doll MA, Rustan TD, Gray K, Feng Y, Ferguson RJ, and Grant DM. Metabolic activation and deactivation of arylamine carcinogens by recombinant human NAT1 and polymorphic NAT2 acetyltransferases. Carcinogenesis. 1993:14: 1633–1638. [PubMed]
109. Agundez JA, Olivera M, Ladero JM, Rodriguez-Lescure A, Ledesma MC, Diaz-Rubio M, Meyer UA, and Benitez J. Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics. 1996;6:501–512. [PubMed]
110. Yu MW, Pai CI, Yang SY, Hsiao TJ, Chang HC, Lin SM, Liaw YF, Chen PJ and Chen CJ. Role of N-acetyltransferase polymorphisms in hepatitis B related hepatocellular carcinoma: impact of smoking on risk. Gut. 2000;47:703–709. [PMC free article] [PubMed]
111. Farker K, Schotte U, Scheele J, and Hoffmann A. Impact of N-acetyltransferase polymorphism (NAT2) in hepatocellular carcinoma (HCC)-an investigation in a department of surgical medicine. Exp Toxicol Pathol. 2003;54:387–391. [PubMed]
112. Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw Y. F, and Chen CJ. Cytochrome P-450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroent. 1995;109:1266–1273. [PubMed]
113. Vahter M. Genetic polymorphism in the biotransformation of inorganic arsenic and its role in toxicity. Toxicol Lett. 2000;112-113:209–217. [PubMed]
114. Marnell LL, Garcia-Vargas GG, Chowdhury UK, Zakharyan RA, Walsh B, Avram MD, Kopplin MJ, Cebrian ME, Silbergeld EK, and Aposhian HV. Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem Res Toxicol. 2003;16:1507–1513. [PubMed]
115. Marcos R, Martinez V, Hernandez A, Creus A, Sekaran C, Tokunaga H, and Quinteros D. Metabolic profile in workers occupationally exposed to arsenic: role of GST polymorphisms. J Occup Environ Med. 2006;48:334–341. [PubMed]
116. Tanaka E, Terada M, and Misawa S. Cytochrome P450 2E1: its clinical and toxicological role. J Clin Pharm Ther. 2000;25:165–175. [PubMed]
117. Morgan K, French SW, and Morgan TR. Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology. 2002;36:122–134. [PubMed]
118. Ho JC, Cheung ST, Leung KL, Ng IO, and Fan ST. Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma. Int J Cancer. 2004;111:494–500. [PubMed]

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