title: Polycyclic aromatic hydrocarbon-DNA adducts in liver tissues of hepatocellular carcinoma patients and controls.
abstract: HCC is a common cancer and HBV and AFB(1) are well-documented, major risk factors. Epidemiologic studies have documented that cigarette smoking also contributes to the development of HCC. PAHs are ubiquitous environmental pollutants and products of incomplete combustion. They are present in both mainstream and sidestream cigarette smoke. PAHs are metabolically activated by phase I enzymes, including CYP1A1, into electrophilic reactants (diol epoxides), which covalently bind to DNA to form adducts. Diol epoxides are also substrates for phase II detoxifying enzymes, including GSTM and GSTP. To examine the association between PAH-DNA adducts and HCC, adduct levels were determined in liver tissue by relative staining intensity with an immunoperoxidase method using a polyclonal antiserum against BPDE-modified DNA. Subjects were also genotyped for polymorphism in several genes involved in the metabolism of PAH, including GSTM1 and GSTP1. Liver tissue was collected from patients with histologically confirmed HCC (n = 105) and from non-HCC controls (n = 37). There was a significant positive correlation (r = 0.3, p < 0.01) between adducts in tumor and adjacent nontumor tissues among HCC cases. The risk of HCC was higher after adjustment for age, sex and HBsAg in the group with the highest tertile tissue levels of PAH-DNA adducts (mean relative nuclear staining intensity of tumor and nontumor tissue > 344) than in the group with the lowest tertile (staining < 241, OR = 3.9, 95% CI = 1.0-14.9). Among non-HCC controls, there were no significant associations between adduct levels and cigarette smoking, GSTM1 null genotype and HBsAg positivity. A strikingly increased HCC risk was observed (OR = 20.3, 95% CI = 5.0-81.8) among HBsAg-positive subjects whose PAH-DNA adduct levels were high (mean relative nuclear staining intensity of tumor and nontumor tissue > 301, median of control tissues) compared to HBsAg-negative subjects who had low PAH-DNA adduct levels. 4-ABP- and AFB(1)-DNA adducts had been measured previously in these same tissues. Subjects with elevated DNA adduct levels of PAH, 4-ABP and AFB(1) had a significantly higher HCC risk with an OR of 36.7 (95% CI 7.2-187.2) compared to those who had low DNA adduct levels. These results suggest that PAHs may play a role in human hepatocarcinogenesis in conjunction with HBsAg carrier status, GSTM1 and GSTP1 genotypes and exposure to 4-ABP and AFB(1).
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY 10032, USA.
authors.forename: Shu-Yuan
authors.initials: SY
authors.lastname: Chen
authors.forename: Li-Yu
authors.initials: LY
authors.lastname: Wang
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Lunn
authors.forename: Wei-Yann
authors.initials: WY
authors.lastname: Tsai
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Chue-Shue
authors.initials: CS
authors.lastname: Lee
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Chen
authors.forename: Regina M
authors.initials: RM
authors.lastname: Santella
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016022:Case-Control Studies; D018736:DNA Adducts / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors
chemical_list: D018736:DNA Adducts; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D006514:Hepatitis B Surface Antigens; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; C095911:polycyclic aromatic hydrocarbons-DNA adduct; C496556:GSTP1 protein, human