Genetic polymorphism of drug metabolizing enzymes in association with risk of bile duct cancer.

Cholangiocarcinoma (CCA) is the most common cancer in endemic areas of liver fluke infection. Although the liver fluke is recognized as a carcinogenic agent in cholangiocarcinogenesis, other factors may play important roles in bringing about the high prevalence of the cancer in populations of this region. Drug metabolizing enzymes (DME) are essential for detoxification of toxic and carcinogenic chemicals. Moreover, DME can play an alternative role by activating chemicals to more toxic metabolites. The large variation of DME activity among individuals is partly due to polymorphism of the genes encoding enzymes. Defective or variant alleles of DME genes may modify the risk of cancer in those who are exposeed to carcinogenic agents. The focus in this review is 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-transferase M1 (GSTM1), GSTT1, GSTO1 and methylenetetrahydrofolate reductase (MTHFR). Mutant alleles which have been 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 genes modify the risk of cancer potentially by interaction and exposure with certain environmental conditions, thereby altering the metabolism of causative agents.