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Vol. 280, Issue 3, 1463-1470, 1997
Department of Pathology, University of California in Irvine,
Irvine, California
Recently nitric oxide (NO) was suggested as a final mediator of
down-regulation of cytochrome P450 by bacterial lipopolysaccaride (LPS). One proposed mechanism is based on the ability of NO to effectively bind to cytochrome P450 heme iron. However, other evidences
exist demonstrating down-regulation of P450 proteins by LPS as well as
by different cytokines. Therefore, it is the purpose of our study to
investigate the relationship between NO and different P450 proteins in
rat liver. One group of Sprague-Dowley rats was treated with LPS for 24 hr and another group was given NO synthase inhibitors,
NG-nitro L-arginine methyl ester or
aminoguanidine at 0, 3, 6, 10 and 20 hr after LPS. LPS treatment caused
a 20-fold increase in plasma nitrates, which was almost completely
abolished by NO synthase inhibitors. LPS caused a substantial
inhibition of the activities of 16
- and 6
-androstenedione
hydroxylation, 7-ethoxyresorufin- and
7-pentoxyresorufin-O-dealkylation (EROD, PROD) that was
fully prevented by cotreatment with NG-nitro
L-arginine methyl ester and aminoguanidine. Western
blotting showed that the apoproteins of 3A2, 2C11, 1A2 and 2B1/2 were
suppressed and NOS inhibitors showed from 29% (3A2) to 100% (2C11)
protection of corresponding apoprotein from suppression by LPS. The
changes in apoprotein were largely due to changes in corresponding mRNA levels, as demonstrated by Northern blotting. Thus, NO appears to be
one of the mediators of the inhibition of 2C11, 3A2, 1A2 and 2B1/2
isozymes by LPS in rat liver.
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