INDUCTION OF CYTOCHROME-P450 2A6 EXPRESSION IN HUMANS BY THE CARCINOGENIC PARASITE INFECTION, OPISTHORCHIASIS-VIVERRINI

The purpose of this study was to examine in vivo the activity of cytoc hrome P450 (CYP) 2A6, an enzyme capable of activating carcinogens, inc luding N-nitrosodimethylamine, in humans with the carcinogenic liver f luke infection, opisthorchiasis viverrini, before and after treatment with the antiparasitic agent, praziquantel. Coumarin hydroxylase activ ity of CW 2A6 was assessed by administering a probe drug, coumarin, an d measuring its metabolite, 7-hydroxycoumarin, in urines collected bet ween 0-2 h and 2-4 h of 106 people with varying intensities of Opistho rchis viverrini infection, Five individuals who did not excrete any de tectable 7-hydroxy coumarin (and have a genetic defect probably leadin g to an absence of catalytic activity of the CYP 2A6 protein) were exc luded from analysis, Infected people excreted an average of 22.7 mu mo l of 7-hydroxycoumarin in the first 2 h after taking the drug, whereas the mean of the uninfected group was 19.4 mu mol; this difference did not reach statistical significance (P = 0.10), However, a highly sign ificant increase in CYP 2A6-related activity was observed in infected individuals who also had radiological evidence of biliary fibrosis (28 .1 mu mol) compared to those without (19.4 mu mol; P = 0.01), Reassess ments of coumarin hydroxylase activity of CYP 2A6 made 2 months after praziquantel treatment showed highly significant reductions in the amo unt of 7-hydroxycoumarin excreted among the infected groups but no dif ference in the uninfected group, These results suggest that expression of CW 2A6 is induced among chronically infected people who also have fibrosis of the intrahepatic bile duct, As already demonstrated in an animal model and now observed in humans for the first time, this incre ase in CW 2A6-related enzyme activity may represent an important mecha nistic link between inflammatory products of chronic liver fluke infec tion (e.g., DNA alkylation damage from endogenously formed N-nitrosami nes) and the high risk of cholangiocarcinoma faced by infected individ uals.