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MECHANISMS OF CYTOKINE‐MEDIATED, POSTTRANSCRIPTIONAL CYP3A1 DOWN‐REGULATION IN PRIMARY RAT HEPATOCYTES
Author(s) -
Lee ChoonMyung,
Morgan Edward T
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a195-c
Subject(s) - p38 mitogen activated protein kinases , microbiology and biotechnology , cytokine , kinase , signal transduction , mapk/erk pathway , ask1 , nitric oxide synthase , biology , chemistry , protein kinase a , nitric oxide , mitogen activated protein kinase kinase , endocrinology , immunology
The enzyme activities and expression of many cytochrome P450s are down‐regulated during inflammation. We recently observed that down‐regulation of CYP2B protein by the inflammatory cytokine interleukin (IL)‐1β is nitric oxide (NO) dependent, and occurs via polyubiquitination and the proteasomal degradation pathway. Here we examined the mechanism of down‐regulation of CYP3A1. In cultured rat hepatocytes, phenobarbital‐induced CYP3A1 protein was rapidly down‐regulated by IL‐1β‐stimulation, to 50% of control within 6 h. This occurred prior to CYP3A1 mRNA down‐regulation. IL‐6, an inflammatory cytokine that did not stimulate NO production, also showed CYP3A1 protein down‐regulation within 24 h. The down‐regulation of CYP3A1 evoked by IL‐1β was not affected by the NOS inhibitor N‐methyl‐L‐arginine, or by proteasomal inhibitors, demonstrating that CYP3A1 down‐regulation is NO‐ and proteasome‐independent. The role of p38‐MAP kinase, a common downstream mediator of both IL‐1β and IL6 signaling, in the down‐regulation was investigated. The p38‐MAP kinase inhibitor SB203580, but not the JNK inhibitor SP600125 nor the MEK inhibitor SP600125, inhibited the down‐regulation of CYP3A by IL‐1β stimulation. Our findings suggest that IL‐1β– and IL6–stimulated down‐regulation of CYP3A involves signaling via p38‐MAP kinase, but not ERK or JNK. This research was supported by NIH grant GM 069971