Effects of T‐ and B‐Cell Deficiency on Regulation of Hepatic P450 Enzymes in Mice Infected With an Intestinal Pathogen

Abstract

Infections and inflammatory stimuli selectively regulate cytochrome P450 (P450) gene expression in the liver. While much attention has been devoted to the roles of the innate immune system and proinflammatory cytokines in this regulation, the influence of the adaptive immune system on the observed effects has not been addressed. Here, we address this question in severe combined immune deficiency (SCID) mice, which are deficient in T‐ and B‐cells. Female SCID or wild‐type mice in a C57BL/6 (B6) background were infected orally with C. rodentium, and hepatic P450 expression was studied 7 days later at the peak of infection. B6 and SCID mice were not different in colonic bacterial colonization or colonic mucosal hypertrophy, but SCID mice had 6‐fold higher levels of bacteria in their livers. Cyp4a10 and Cyp2b9 down‐regulation was attenuated in the SCID mice, while the regulation of other P450s was similar in the two strains. In mice with a C3H genetic background, the SCID mutation also blocked the down‐regulation of Cyp3a11 and Cyp2c29. These results indicate that bacterial translocation to the liver is not the cause of drug metabolizing enzyme down‐regulation, and suggest that B‐cells, T‐cells or their derived cytokines may have direct or indirect roles in the regulation of some hepatic P450 enzymes during infection. Supported by National Institutes of Health grant R01DK072372.