The purpose of this study was to examine in vivo the activity of
cytochrome P450 (CYP) 2A6, an
enzyme capable of activating
carcinogens, including
N-nitrosodimethylamine, in humans with the carcinogenic liver fluke
infection,
opisthorchiasis viverrini, before and
after treatment with the
antiparasitic agent,
praziquantel.
Coumarin hydroxylase activity of CYP 2A6 was assessed by administering a probe
drug,
coumarin, and measuring its metabolite,
7-hydroxycoumarin, in urines collected between 0-2 h and 2-4 h of 106 people with varying intensities of
Opisthorchis viverrini infection. Five individuals who did not excrete any detectable 7-hydroxy
coumarin (and have a genetic defect probably leading to an absence of catalytic activity of the CYP 2A6
protein) were excluded from analysis. Infected people excreted an average of 22.7 mumol of
7-hydroxycoumarin in the first 2 h after taking the
drug, whereas the mean of the uninfected group was 19.4 mumol; this difference did not reach statistical significance (P = 0.10). However, a highly significant increase in CYP 2A6-related activity was observed in infected individuals who also had radiological evidence of biliary
fibrosis (28.1 mumol) compared to those without (19.4 mumol; P = 0.01). Reassessments of
coumarin hydroxylase activity of CYP 2A6 made 2 months after
praziquantel treatment showed highly significant reductions in the amount of
7-hydroxycoumarin excreted among the infected groups but no difference in the uninfected group. These results suggest that expression of CYP 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 increase in CYP 2A6-related
enzyme activity may represent an important mechanistic link between inflammatory products of chronic liver fluke
infection (e.g.,
DNA alkylation damage from endogenously formed N-
nitrosamines) and the high risk of
cholangiocarcinoma faced by infected individuals.