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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Nitric oxide-dependent proteasomal degradation of cytochrome P450 2B proteins.

Authors: Lee, Choon-Myung; Kim, Bong-Yoon; Li, Lian; Morgan, Edward T

Published In J Biol Chem, (2008 Jan 11)

Abstract: Exposure to inflammatory agents or cytokines causes the suppression of cytochrome P450 (CYP) enzyme activities and expression in liver and primary hepatocyte cultures. We showed previously that phenobarbital-induced CYP2B protein is down-regulated in primary cultures of rat hepatocytes after exposure to bacterial endotoxin (lipopolysaccharide) in a nitric oxide (NO) -dependent manner. In this study, we found that CYP2B proteins in primary rat hepatocyte cultures were suppressed >60% after 6 h of treatment with interleukin-1beta (IL-1). This effect was NO-dependent, and treatment of cells with the NO donors (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) aminodiazen-1-ium-1,2-diolate (NOC-18), S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine also suppressed CYP2B proteins. However, the down-regulation by IL-1 was insensitive to inhibition of cGMP-dependent protein kinases. The down-regulation by IL-1 or NO donors was abolished by treatments with the proteasome inhibitors MG132 and lactacystin that did not affect NO production. The calpain inhibitor E64-d or the lysosomal protease inhibitors NH(4)Cl and chloroquine did not attenuate the down-regulation of CYP2B by IL-1. Treatment of HeLa cells expressing c-Myc-tagged CYP2B1 with NOC-18 down-regulated its expression and enhanced its ubiquitination. Treatment of rat liver microsomes with S-nitrosoglutathione caused S-nitrosylation of CYP2B protein and enhanced the ubiquitination pattern of CYP2B compared with unmodified CYP2B in an in vitro ubiquitination assay. These data are consistent with the hypothesis that NO-dependent CYP2B ubiquitination and proteasomal degradation are dependent on protein modification by reactive nitrogen species.

PubMed ID: 17993647 Exiting the NIEHS site

MeSH Terms: Animals; Cytochrome P-450 CYP2B1/metabolism; Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism*; Hepatocytes/enzymology*; Interleukin-1/pharmacology; Interleukin-6/pharmacology; Kinetics; Male; Microsomes, Liver/enzymology*; Nitric Oxide/pharmacology*; Proteasome Endopeptidase Complex/drug effects; Proteasome Endopeptidase Complex/metabolism*; Rats; Rats, Sprague-Dawley; Transcription, Genetic

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