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Regulation of cytochrome P450 4F11 by nuclear transcription factor-?B.
Drug Metab Dispos. 2012 Jan;40(1):205-11
Authors: Bell JC, Strobel HW
Abstract
Although the mechanisms that regulate CYP4F genes have been and are currently being studied in a number of laboratories, the specific mechanisms for the regulation of these genes are not yet fully understood. This study shows that nuclear factor ?B of the light-chain-enhancer in activated B cells (NF-?B) can inhibit CYP4F11 expression in human liver carcinoma cell line (HepG2) as summarized below. Tumor necrosis factor-? (TNF-?), a proinflammatory cytokine, has been shown to activate NF-?B signaling while also activating the c-Jun NH(2)-terminal kinase (JNK) signaling pathway. Other studies have reported that JNK signaling can up-regulate CYP4F11 expression. The results of this study demonstrate that in the presence of TNF-? and the specific NF-?B translocation inhibitor N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD-0354), there is a greater increase in CYP4F11 expression than that elicited by TNF-? alone, indicating that NF-?B plays an inhibitory role. Moreover, NF-?B stimulation by overexpression of mitogen-activated protein kinase kinase kinase inhibited CYP4F11 promoter expression. CYP4F11 promoter inhibition can also be rescued in the presence of TNF-? when p65, a NF-?B protein, is knocked down. Thus, NF-?B signaling pathways negatively regulate the CYP4F11 gene.
PMID: 22011441 [PubMed - indexed for MEDLINE]
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