INCREASED OXIDATIVE DNA-DAMAGE AND HEPATOCYTE OVEREXPRESSION OF SPECIFIC CYTOCHROME-P450 ISOFORMS IN HEPATITIS OF MICE INFECTED WITH HELICOBACTER-HEPATICUS

A recently discovered bacterium, Helicobacter hepaticus, infects the i ntrahepatic bile canaliculi of mice, causing a severe chronic hepatiti s culminating in liver cancer, Thus, it affords an animal model for st udy of bacteria-associated tumorigenesis including H. pylori-related g astric cancer, Reactive oxygen species are often postulated to contrib ute to this process, We now report that hepatitis of male mice infecte d with H. hepaticus show significant increases in the oxidatively dama ged DNA deoxynucleoside 8-hydroxydeoxyguanosine, with the degree of da mage increasing with progression of the disease. Perfusion of infected livers with nitro blue tetrazolium revealed that superoxide was produ ced in the cytoplasm of hepatocytes, especially in association with pl asmacytic infiltrates near portal triads, Contrary to expectations, Ku pffer cells, macrophages, and neutrophils were rarely involved. Howeve r, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in man y cells, concomitant with severe hepatitis, The CYP2A5 immunohistochem ical staining co-localized with formazan deposits resulting from nitro blue tetrazolium reduction and occurred in nuclei as well as cytoplas m, These findings suggest that CYP2A5 contributes to the superoxide pr oduction and 8-hydroxydeoxyguanosine formation, although reactive oxyg en species from an unknown source in the hepatocytes leading to CYP2A5 induction or coincidental occurrence of these events are also possibi lities, Three glutathione S-transferase isoforms, mGSTP1-1 (pi), mGSTA 1-1 (YaYa), and mGSTA4-4, also showed striking increases evidencing ma jor oxidative stress in these livers.