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Vol. 280, Issue 3, 1445-1454, 1997
Departments of
Pharmacology, Emory University School of Medicine,
Atlanta, Georgia (M.B.S., E.T.M.) and
Oregon Health Sciences University
School of Medicine, Portland, Oregon (D.R.K.)
Inflammatory stimuli such as bacterial lipopolysaccharide (LPS) have
been shown to down-regulate the mRNA and protein expression of hepatic
cytochrome P-450 (P-450) isozymes 2C11, 2C12, 2E1 and 3A2 and to induce
the mRNA expression of the P-450 4A subfamily. In this study, we
examined the effects of irritants on the hepatic and renal expression
of P-450 2C11, 2E1 and 3A2 and the 4A subfamily in the rat. Fischer 344 rats were administered doses of SiO2 (Celite), BaSO4, kaolin and LPS intraperitoneally and killed after
different times for hepatic and renal RNA and microsome isolation. The
administration of each irritant was found to suppress hepatic P-450
2C11 mRNA and protein and to induce P-450 4A1, 4A2 and 4A3 mRNA
expression while having no significant effect on P-450 2E1 or 3A2.
P-450 4A2, 4A3 and 2E1 mRNAs were all induced in the kidney cortices of
the irritant- and LPS-treated rats. The effects of BaSO4
and SiO2 were found to be dose dependent.
Chlorzoxazone-6-hydroxylase activity increased in the kidneys of
irritant-treated rats, which is consistent with an increased expression
of P-450 2E1. All irritants were found to induce the mRNA for the
acute-phase protein fibrinogen; however, in contrast to LPS treatment,
none of the irritants that were tested induced hepatic inducible nitric
oxide synthase mRNA expression. These findings demonstrate the
induction of renal P-450 isozymes after irritant and LPS
administration. The findings of this study also suggest that different
inflammatory stimuli affect the individual P-450 isozymes
differentially.
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