The liver pathogen Helicobacter hepaticus has provided the first animal model for study of mechanisms of bacteria- related cancer. Information obtained with this model will contribute significantly to understanding of the pathogenesis of human liver cancer, a prevalent form of cancer in many countries, of gastric cancer associated with H. pylori, and of other cancers thought to be sometimes a consequence of infection, such as those of urinary bladder and colon. We have been testing the hypothesis that an infection-related increase in reactive oxygen species (ROS) contributes to H. hepaticus-associated liver tumorigenesis. Significant increases in the levels of the promutagenic altered DNA base 8-hydroxydeoxyguanosine, caused by ROS, have been detected in both naturally- and experimentally-infected livers, at all stages of infection. Although a likely source of these was thought to be Kupffer cells or inflammatory neutrophils, few of these cell types were observed in the infection-related infiltrates. An alternative hypothesis, that upregulation of cytochromes P450 (CYP) in the hepatocytes was responsible, has been substantiated by demonstration of significant increases in both CYP1A2 and 2A5, by enzyme assay, immunohistochemistry, and immunoblot analysis. Both levels of these CYP proteins in individual cells, and number of positive cells, showed increases. Furthermore, liver perfusion with nitro blue tetrazolium (NBT) followed by CYP immunohistochemistry showed co-localization of upregulated CYP2A5 and formazan precipitate resulting from ROS reduction of NBT. These changes occurred typically in the vicinity of periportal or diffuse leukocyte infiltrates, suggesting a role for cytokines in the CYP upregulation and ROS release.