Genetic Polymorphism of Drug Metabolizing Enzymes inAssociation with Risk of Bile Duct Cancer


Cholangiocarcinoma (CCA) is the most common cancer in endemic areas of liver fluke infection. Althoughthe liver fluke is recognized as a carcinogenic agent in cholangiocarcinogenesis, other factors may play importantroles in bringing about the high prevalence of the cancer in populations of this region. Drug metabolizingenzymes (DME) are essential for detoxification of toxic and carcinogenic chemicals. Moreover, DME can play analternative role by activating chemicals to more toxic metabolites. The large variation of DME activity amongindividuals is partly due to polymorphism of the genes encoding enzymes. Defective or variant alleles of DMEgenes may modify the risk of cancer in those who are exposeed to carcinogenic agents. The focus in this reviewis on DME genes which have been reported to be associated with CCA risk. These include CYP1A2, arylamine-N-acetyltransferase-1 (NAT1) and NAT2, NADPH-quinone oxidorecutase-1 (NQO1), glutathione-S-transferaseM1 (GSTM1), GSTT1, GSTO1 and methylenetetrahydrofolate reductase (MTHFR). Mutant alleles which havebeen reportedly associated with an increased risk include CYP1A2*1F, GSTT1 null, GSTO1 and MTHFR 677C>T,whereas, slow NAT2 and NQO1*2 decrease risk and NAT1 variants and GSTM1 null have no effect. These genesmodify the risk of cancer potentially by interaction and exposure with certain environmental conditions, therebyaltering the metabolism of causative agents.