Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus

Mice naturally infected by Helicobacter hepaticus develop a chronic activehepatitis leading to hepatocellular carcinoma. This mouse model of livercancer was used to examine the impact of bacterial infection on the hepaticexpression and activity of enzymes involved in carcinogen bioactivation(phase I enzymes) and detoxification (phase II enzymes). No majordifferences in total cytochrome P450 (CYP) content were found betweencontrol and infected mice during the course of the study. The most strikingmodulations of individual isoenzymes were the increases inimmunohistochemical staining observed for CYP1A and CYP2A5 in relation toincreasing age and liver lesions. The increase in CYP2A5 in mice aged over12 months was confirmed by the observed increases in coumarin7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels byNorthern blot analysis. Immunoblotting confirmed the specific induction ofCYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver withnitroblue tetrazolium, an indicator for superoxide formation, demonstratedthat in livers of infected mice, hepatocytes often co-expressed CYP2A5 andformazan deposition. Concerning phase II enzymes, an enhancement ofglutathione S-transferase (GST) activities, related to the disease process,was observed in infected mice. An age- specific increase of GSTpi and A4.4(early stage of disease) and GST YaYa (>9 months) expression was alsodemonstrated by immunohistochemical staining. In contrast, catalase andglutathione- peroxidase activities, as well as reduced glutathione contentwere decreased in the early stages of disease (3-9 months) in infected micecompared to age-matched control mice. Overall, these results suggest thatalterations in CYP and GST expression may contribute to the aetiology oftumour incidence due to H. hepaticus infection via production of reactiveoxygen species.