Nitric oxide-dependent CYP2B degradation is potentiated by a cytokine-regulated pathway and utilizes the immunoproteasome subunit LMP2

• Type of Material: Article
• Authors: Haiyan Sun, Emory University; Choon-Myung Lee, Emory University; Shweta Tripathi, Emory University; Kyung-Bo Kim, University of Kentucky; Edward T Morgan, Emory University
• Language: English
• Date: 2012-05-22
• Publisher: Portland Press
• Publication Version: Final Published Version
• Copyright Statement: © 2012 The Author(s)
• License: Creative Commons Attribution-NonCommercial 2.5 Generic
• Final Published Version (URL): http://www.biochemj.org/bj/445/bj4450377.htm
• Title of Journal or Parent Work: Biochemical Journal
• ISSN: 0264-6021
• Volume: 2012
• Issue: 445
• Start Page: 377
• End Page: 382
• Grant/Funding Information: This work was supported by the National Institutes of Health [grant numbers GM069971 (to E.T.M.) and CA131059 (to K-B.K.)] and by the 2011 Natural Science Foundation of Guangdong Province, China [grant number S2011010004456].
• Keywords: interleukin-1 (IL-1); cytochrome P450; proteasome; nitric oxide (NO); immunoproteasome
• Research Categories: Chemistry, Pharmaceutical; Chemistry, Biochemistry; Health Sciences, Pharmacology

Abstract

CYP2B proteins in rat hepatocytes undergo NO-dependent proteolytic degradation, but the mechanisms and the reasons for the specificity towards only certain P450 enzymes are yet unknown. Here, we found that down-regulation of CYP2B proteins by the NO donor NOC-18 is accelerated by pretreatment of the hepatocytes with interleukin-1β (IL-1) in the presence of a nitric oxide synthase inhibitor, suggesting that an NO-independent action of IL-1 contributes to the lability of CYP2B proteins. The immunoproteasome subunit LMP2 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.