DOWN-REGULATION OF CYTOCHROME-P450 MESSENGER-RNAS AND PROTEINS IN MICE LACKING A FUNCTIONAL NOS2 GENE

Endotoxemia results in both the down-regulation of multiple cytochrome P450 genes and the induction of inducible nitric oxide synthase (NOS2 ). The nitric oxide (NO) released during inflammation has been implica ted as the mediator of the decreased catalytic activity and expression of several cytochrome P450 isozymes. We examined the role of NO in th e decreases in both gene expression and activity of three P450s in end otoxemic parental and NOS2 knockout mice. Twenty-four hours of endotox in (LPS) treatment significantly suppressed CYP2C29 and CYP3A11 mRNA e xpression in both the parental and NOS2 knockout strains. Microsomal C YP2E1, CYP2C-like, and CYP3A-like protein levels were also decreased i n both strains of mouse. Similar results were obtained in parental str ain endotoxemic mice cc-administered the NOS inhibitor aminoguanidine. Six hours after LPS treatment, there was an NO-dependent decrease in testosterone Gp-hydroxylase activity, because no decreases in activity were observed in the NOS2 knockout mice or in mice co-administered am inoguanidine. LPS also evoked decreases in testosterone 15 alpha- and 16 beta-hydroxylase activity after 24 hr that were observed in the par ental strain and not in NOS2 knockout mice. Our results demonstrate th at the down-regulation of CYP2C-like, CYP3A-like and CYP2E1 proteins a nd mRNAs, in the endotoxemic mouse can occur independently of NO produ ction. We do, however, show that the NO released during endotoxemia is capable of causing decreases in some cytochrome P450 catalytic activi ties.