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Vol. 54, Issue 2, 273-279, August 1998
Department of Pharmacology, Emory University School of Medicine,
Atlanta, Georgia 30322
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 implicated
as the mediator of the decreased catalytic activity and expression of
several cytochrome P450 isozymes. We examined the role of NO in the
decreases in both gene expression and activity of three P450s in
endotoxemic parental and NOS2 knockout mice. Twenty-four hours of
endotoxin (LPS) treatment significantly suppressed CYP2C29 and CYP3A11
mRNA expression in both the parental and NOS2 knockout strains.
Microsomal CYP2E1, CYP2C-like, and CYP3A-like protein levels were also
decreased in both strains of mouse. Similar results were obtained in
parental strain endotoxemic mice co-administered the NOS inhibitor
aminoguanidine. Six hours after LPS treatment, there was an
NO-dependent decrease in testosterone 6
-hydroxylase activity,
because no decreases in activity were observed in the NOS2 knockout
mice or in mice co-administered aminoguanidine. LPS also evoked
decreases in testosterone 15
- and 16-hydroxylase activity after
24 hr that were observed in the parental strain and not in NOS2
knockout mice. Our results demonstrate that the down-regulation of
CYP2C-like, CYP3A-like and CYP2E1 proteins and mRNAs, in the
endotoxemic mouse can occur independently of NO production. We do,
however, show that the NO released during endotoxemia is capable of
causing decreases in some cytochrome P450 catalytic activities.
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