Association of liver fluke (Opisthorchis viverrini) infestation with increased expression of cytochrome P450 and carcinogen metabolism in male hamster liver.
Synergy between exposure to chemical carcinogens (nitrosamines) and infestation with the liver fluke Opisthorchis viverrini has been demonstrated in a hamster model of hepatocarcinogenesis (Flavell et al., Carcinogenesis 4:927-930, 1983; Thamavit et al., Carcinogenesis 8:1351-1353, 1987). To elucidate the mechanisms of this interaction we tested the hypothesis that liver parasitism might influence the expression and activity of carcinogen metabolizing enzymes. We found that one, and perhaps more, hamster liver cytochrome P450 (CYP) isozymes immunorelated to mouse CYP2A5 contributed up to 50 or 60% of the hepatic aflatoxin B1 (AFB) and N-nitrosodiethylamine (NDEA) metabolism, respectively. As inferred from average enzyme activities and from western blot, immunoinhibition, and substrate (coumarin) inhibition analyses, O. viverrini infestation increased the expression of enzymes detectable by anti-CYP2A5 antibody as well as NDEA metabolism in male but not in female hamsters. Immunohistochemical analysis of CYP2A expression by anti-mouse CYP2A5 antibody demonstrated that the O. viverrini-associated increase was not uniformly distributed throughout the liver but occurred in hepatocytes immediately adjacent to areas of inflammation. Immunohistochemical analysis of AFB-DNA adducts in the livers of O. viverrini-infested hamsters treated with AFB showed that the highest levels of adducts were found in the regions of liver where hepatocellular expression of enzymes detectable by anti-CYP2A5 antibody is induced. These results suggest that a high local expression of CYP isozymes in O. viverrini-infested livers could be a contributing risk factor in the development of liver cancers associated with parasitic hepatitis.
Kirby
G M
GM
Lady Davis Institute for Medical Research, Montreal, Canada.
Pelkonen
P
P
Vatanasapt
V
V
Camus
A M
AM
Wild
C P
CP
Lang
M A
MA
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003003:Clonorchiasis / Q000378:metabolism*; D006224:Cricetinae; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D018736:DNA Adducts / Q000032:analysis; D004052:Diethylnitrosamine / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008297:Male; D008647:Mesocricetus; D006899:Mixed Function Oxygenases / Q000276:immunology / Q000378:metabolism; D012307:Risk Factors
D018736:DNA Adducts; D004052:Diethylnitrosamine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2