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Vol. 287, Issue 1, 352-358, October 1998
Department of Pharmacology, 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 of both gene expression and activity of three major P450s in
the endotoxemic Fischer 344 rat. Endotoxin (LPS) treatment suppressed
both mRNA and protein expression of P450 2C11, 2E1, and 3A2.
Coadministration of the NOS inhibitor aminoguanidine to LPS-treated
rats completely inhibited the release of NO into the plasma but did not
reverse the down-regulation of expression of any of the P450s examined
at three time points. LPS treatment had a biphasic effect on some P450
catalytic activities. The hydroxylation of testosterone at the 2
-,
16- and to a lesser extent 6
-positions, was inhibited 6 hr after
LPS treatment and returned to normal by 12 hr. The role of NO in the 6 hr effects could not be assessed due to effects of the aminoguanidine
treatment itself. The second phase of decreased P450 activities seen
after 24 hr was attributed to the NO-independent decrease in gene
expression. Our results suggest that NO is not required for the
LPS-evoked down-regulation of P450 2C11, 2E1 and 3A2 mRNA or protein
expression. We cannot rule out a possible role for NO in the decreases
in P450 activities seen early in the response.
0022-3565/98/2871-0352$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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