Lack of association between the functional polymorphisms in the estrogen-metabolizing genes and risk for hepatocellular carcinoma.
ABSTRACT Estrogens have been proposed to act as tumor promoters and induce hepatocarcinogenesis. Recently, we observed a significant association between the risk for hepatocellular carcinoma and the polymorphisms of the estrogen receptor (ESR) alpha (ESR1) gene, supporting the hypothesis of involvement for the estrogen-ESR axis in the estrogen-induced hepatocarcinogenesis. In this study, based on another hypothesis in which estrogen metabolites can directly cause DNA damage and affect tumor initiation, we examined whether the polymorphisms of the estrogen-metabolizing enzymes (EME), which are involved in biogenesis (CYP17, CYP19), bioavailability (CYP1A1, CYP1B1), and degradation (catechol-O-methyltransferase) of the estrogens, have any bearing on the risk for hepatocellular carcinoma. Seven functional polymorphisms in five EMEs (CYP17 MspAI site, CYP19 Trp39Arg, Ile462Val and MspI site in CYP1A1, CYP1B1 Val432Leu, and Ala72Ser and Val158Met in catechol-O-methyltransferase) were genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PCR-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk for hepatocellular carcinoma was observed with the seven polymorphisms in hepatitis B virus carriers and non-hepatitis B virus carriers after correction for multiple comparisons. After stratification by common confounding factors of hepatocellular carcinoma, the EME polymorphism remained no significant association with the hepatocellular carcinoma risk. Furthermore, no signs of gene-gene interactions were observed for each combination of the seven polymorphisms. Our findings suggest that the polymorphisms of EMEs may not contribute significantly to the risk for hepatocellular carcinoma.
Article: Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk.[show abstract] [hide abstract]
ABSTRACT: The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.Archives of Industrial Hygiene and Toxicology 07/2009; 60(2):217-42. · 1.05 Impact Factor