Cancer risk can be influenced by the exposure to endogenous or environmental toxins. Polymorphic enzymes involved in the metabolic activation/detoxification of carcinogens may account for individual variations of risk. We studied the polymorphisms of five enzymes of the P450 superfamily, CYP1A1, CYP1A2, CYP2D6, CYP2E1 and CY3A4, as risk factors for liver disease progression and cancer in hepatitis C virusinfected patients. CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR. Different stages of disease were considered, as follows: 90 asymptomatic carriers and 87 chronic hepatitis, 92 cirrhosis and 91 hepatocellular carcinoma (HCC) cases. Reference allele frequencies were obtained from 99 blood donors. Allele distributions among categories were compared using the 2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to express relative risks. Independent associations were modeled by correspondence analysis and logistic regression. Frequencies of the CYP1A1 highly inducible alleles, MspI m2 and Val, were increased in liver disease patients compared with carriers; no specific association with HCC was found. The high-activity CYP2E1 c2 allele was underrepresented among HCC patients with respect to other HCV categories, including cirrhosis. CYP2D6 poor metabolizer (PM) genotypes were significantly more frequent in healthy subjects (7.1%) and carriers (11.1%) than in hepatitis/cirrhosis (4.6%) and HCC (1.2%) patients. This was confirmed by multivariable analysis. PM genotypes protected against progressive disease as ORs reduced proportionally to stage. The age at diagnosis for HCC was anticipated in non-PM individuals. No differences were seen for CYP1A2 and CYP3A4 genes. Polymorphic variants of CYP genes may contribute to the progression of liver disease and HCC risk in HCV-infected subjects. © 2003 Wiley-Liss, Inc. Key words: drug-metabolizing enzymes; DNA polymorphism; chronic liver disease; genetic susceptibility Hepatocellular carcinoma (HCC) ranks fifth among causes of cancer mortality worldwide and is responsible for approximately 1 million deaths yearly. 1 HCC almost invariably arises in the setting of chronic progressive liver diseases, in particular, chronic infections by hepatitis B and C viruses. 2,3 Hepatitis C virus (HCV) infection is presently the major cause of chronic liver disease in the West, and it is associated with over 80% of HCC cases in Italy, 4 where there are an estimated 2 million HCV-infected patients. 5 In about 20% of patients, chronic hepatitis C progresses to cirrhosis, 6 which is complicated by HCC development at a yearly rate of approximately 2.5%. 7 As in other tumor models, there is considerable experimental and epidemiologic evidence indicating that HCC development is a multistage process to which multiple risk factors contribute, such as age, sex, alcohol consumption, tobacco smoke and viral heterogeneity however, these variables do not fully account for the observed clinical var...

Factors influencing the progression of liver disease and the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection are poorly understood. Inherited variations of drug-metabolizing enzyme (DME) activities may affect liver damage and cancer risk by modifying individual susceptibility to endogenous or exogenous toxic compounds. We investigated the association of liver disease severity with common alleles of microsomal epoxide hydrolase (mEH), an enzyme involved in the metabolism of highly reactive epoxide intermediates. Three polymorphisms (Tyr113His, His139Arg, and ؊613C/T) were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) in 394 patients at different stages of disease, including 92 asymptomatic carriers, 109 patients with chronic hepatitis, 100 patients with cirrhosis, and 93 patients with HCC. Reference allele frequencies were obtained from 99 healthy blood donors. Allele distributions between categories were compared using the 2 test; odds ratios (ORs) and 95% CI were calculated to express relative risks. Allele frequencies among 99 healthy controls were as follows: 15.1% for 113His/His, 4.0% for 139Arg/Arg, and 46.5% for ؊613C/T. mEH 113His/His homozygotes were overrepresented in advanced stages of disease, in particular among HCC patients (27.9%; P ‫؍‬ .03; OR, 2.2; 95% CI, 1.0-4.6). Differences were more pronounced among men and between extreme patient categories. When mEH genotypes were combined to express a metabolic phenotype, very slow metabolizers were highly prevalent among cirrhotic and HCC patients (18% vs. 3.3% in carriers; P < .001). In conclusion, mEH gene polymorphisms were significantly associated with HCV-related liver disease severity and HCC risk. Men were at higher risk than women; this might be explained by hormonal regulation of gene expression or by differential exposure to environmental toxins. (HEPATOLOGY 2002;36:195-201.) T he worldwide burden of deaths caused by liver diseases and liver cancer, which usually arises in the setting of cirrhosis and chronic viral hepatitis, is estimated to be approximately 1.3 million/yr. 1 Chronic hepatitis C virus (HCV) infections account for over 80% of cases of cirrhosis and hepatocellular carcinomas (HCC) in Italy, 2 for which over 2 million anti-HCV-positive cases are estimated. 3 HCV-related liver disease displays a multiplex phenotype in which environmental and viral factors are likely to act in concert with individual susceptibility to induce liver damage. Overall penetration of disease expression is low, because less than 20% of infected individuals will develop cirrhosis over a 20-to 30-year period. 4 Determinants of HCV pathogenesis are barely known and include age at infection, 5 disease duration, 4 sex, 6 modes of transmission, 7 immunogenetic variables, 8 and viral heterogeneity, 9 but these factors account for only a small part of the clinical variability of the disease. Dietary factors, inherited metabolic defects, such as hemochromatosis, 10 and alc...

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