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 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.
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Thailand.
S
S
Satarug
M A
MA
Lang
P
P
Yongvanit
P
P
Sithithaworn
E
E
Mairiang
P
P
Mairiang
P
P
Pelkonen
H
H
Bartsch
M R
MR
Haswell-Elkins
D000704:Analysis of Variance; D000818:Animals; D000980:Antiplatyhelmintic Agents / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D018281:Cholangiocarcinoma / Q000453:epidemiology / Q000209:etiology*; D065637:Cytochrome P-450 CYP2A6; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D006801:Humans; D008109:Liver Diseases, Parasitic / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009889:Opisthorchiasis / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D011223:Praziquantel / Q000627:therapeutic use; D012307:Risk Factors; D013785:Thailand
D000980:Antiplatyhelmintic Agents; D015415:Biomarkers; D011223:Praziquantel; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6