PT  - JOURNAL ARTICLE
AU  - Oleg Khatsenko
AU  - Yutaka Kikkawa
TI  - Nitric Oxide Differentially Affects Constitutive Cytochrome P450 Isoforms in Rat Liver
DP  - 1997 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1463--1470
VI  - 280
IP  - 3
4099  - http://jpet.aspetjournals.org/content/280/3/1463.short
4100  - http://jpet.aspetjournals.org/content/280/3/1463.full
SO  - J Pharmacol Exp Ther1997 Mar 01; 280
AB  - 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 16α- and 6β-androstenedione hydroxylation, 7-ethoxyresorufin- and 7-pentoxyresorufin-O-dealkylation (EROD, PROD) that was fully prevented by cotreatment with NG-nitroL-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. The American Society for Pharmacology and Experimental Therapeutics