title: Nitric oxide-dependent CYP2B degradation is potentiated by a cytokine-regulated pathway and utilizes the immunoproteasome subunit LMP2.
abstract: CYP2B proteins in rat hepatocytes undergo NO-dependent proteolytic degradation, but the mechanisms and the reasons for the specificity towards only certain P450 (cytochrome P450) enzymes are yet unknown. In the present study we found that down-regulation of CYP2B proteins by the NO donor NOC-18 is accelerated by pretreatment of the hepatocytes with IL-1 (interleukin-1β) in the presence of an NO synthase inhibitor, suggesting that an NO-independent action of IL-1 contributes to the lability of CYP2B proteins. The immunoproteasome subunit LMP2 (large multifunctional peptidase 2) was significantly expressed in hepatocytes under basal conditions, and IL-1 induced LMP2 within 6-12 h of treatment. CYP2B protein degradation in response to IL-1 was attenuated by the selective LMP2 inhibitor UK-101, but not by the LMP7 inhibitor IPSI. The results show that LMP2 contributes to the NO-dependent degradation of CYP2B proteins, and suggest that induction of LMP2 may be involved in the potentiation of this degradation by IL-1.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.forename: Choon-myung
authors.initials: CM
authors.lastname: Lee
authors.forename: Shweta
authors.initials: S
authors.lastname: Tripathi
authors.forename: Kyung-Bo
authors.initials: KB
authors.lastname: Kim
authors.forename: Edward T
authors.initials: ET
authors.lastname: Morgan
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051381:Rats; D011916:Rats, Inbred F344; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: C403503:FAM107A protein, human; D007375:Interleukin-1; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; C071313:LMP-2 protein; D009569:Nitric Oxide; D013250:Steroid Hydroxylases; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019331:NG-Nitroarginine Methyl Ester