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

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.

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