Selective Modulation of Hepatic Cytochrome P450 and Flavin Monooxygenase 3 Expression during Citrobacter rodentium Infection in Severe Combined Immune Deficient (SCID) Mice.

Publication Type:

Journal Article

Source:

Drug metabolism and disposition: the biological fate of chemicals (2012)

Abstract:

The profile of selective modulation of hepatic cytochrome P450 (P450) gene expression caused by infection with the murine intestinal pathogen Citrobacter rodentium has been well characterized in multiple genetic backgrounds; yet, the mechanisms underlying this modulation are still not entirely understood. While several studies have addressed the roles of cytokines from the innate immune system, the influence of the adaptive immune system is not known. To address this deficiency, we used mice harboring the severe combined immune deficiency (SCID) spontaneous mutation, which lack mature T and B lymphocytes and are unable to mount an acquired immune response. Female C57BL/6 (B6) and SCID mice were infected orally with C. rodentium and assessed for bacterial colonization/translocation and P450 and flavin monooxygenase-3 (Fmo3) expression levels after 7 days. SCID mice showed similar patterns of colonic bacterial colonization and a similar degree of colonic mucosal hypertrophy when compared to infected B6, but SCID mice displayed 6-fold greater bacterial translocation to the liver. Cyp4a10 and Cyp2b9 down-regulations were partially and fully blocked in the SCID mice, while the regulation of other P450s and Fmo3 was similar in both strains. In the C3H genetic background, the SCID mutation also blocked the down-regulation of Cyp3a11, Cyp3a25, Cyp2d22 and Cyp2c29. The results clearly dissociate bacterial translocation to the liver from hepatic drug metabolizing enzyme regulation, and suggest a possible role of T-cells, T-cell cytokines, or other proteins regulated by such cytokines in the selective regulation of a limited subset of hepatic P450 enzymes during C. rodentium infection.