Changes in Hepatic Cytochrome P450 Expression after Citrobacter rodentium Infection in Cyp4a10- and Cyp4a14-deficient Mice

Previously we reported that following infection with Citrobacter rodentium, the equivalent of enteropathogenic Escherichia coli in humans, murine hepatic cytochrome P450 mRNAs are selectively regulated and that Cyp4a mRNAs were among the most sensitive to down-regulation.  Here we investigate the role of Cyp4a10 or Cyp4a14 in mediating the regulation of P450s of the mouse liver during C. rodentium infection by comparing responses in WT and Cyp4a-deficient mice. In this study either female or male wildtype (WT), Cyp4a10-deficient (Cyp4a10^-/-) or Cyp4a14-deficient (Cyp4a14^-/-) mice were infected orally with C. rodentium and the hepatic expression of several P450s mRNAs were examined seven days later.   In general, the mRNA expression level of untreated female and male Cyp4a-deficient animals were between 20-80% of those found in WT animals, the exception being an almost 3-fold higher expression of Cyp2a5 in male animals of either null genotype when compared with WT.  In all genotypes, when significant sex differences were recorded, generally male animals had lower basal expression levels of mRNAs than female except with Cyp2c29 where WT female and male had similar expression levels but the Cyp4a-deficient males had between 2- and 20-fold higher expression.  During infection, all WT and Cyp4a10-deficient groups of animals behaved similarly in their regulation of Cyp1a2 and 2c29.  In female animals, when compared with WT, the absence of Cyp4a10 attenuated the up-regulation of Cyp2c9.  The up-regulation of Cyp4f18 and down-regulation of Cyp2a5, 2d22, 3a11 and 3a25 seen in WT mice were all abrogated in Cyp4a10^-/- mice.  In male animals, when compared with WT, the absence of Cyp4a10 resulted in the down-regulation of both Cyp2b9 and 2e1 and the up-regulation of Cyp3a13 and 4f18 while the down-regulation of Cyp1a2, 2a5, 2c29 and 2d9 were abrogated.  All WT and Cyp4a14-deficient groups of mice had similar trends in their regulation of Cyp1a2, 2b9, 2d9, 2e1 and 4a10 during infection.  For both female and male animals, when compared to WT, the absence of Cyp4a14 resulted in the up-regulation of Cyp2c29 while the up-regulation of Cyp4f18 and the down-regulation of both Cyp3a11 and 3a25 were abrogated.  While in WT male mice Cyp3a13 was elevated and Cyp2d22 depressed, the absence of Cyp4a14 abrogated these effects.  These results indicate that the presence or absence of Cyp4a10 or Cyp4a14 affects the hepatic response to enteral C. rodentium infection reflected in the differential but overlapping impacts of Cyp4a10 and Cyp4a14 genotypes in the regulation of P450 mRNAs. We speculate that these results may indicate a broader role of Cyp4as in the response to infection.