Posttranscriptional elevation of cytochrome P450 3A expression.
Human CYP3A, the most abundant hepatic and intestinal cytochrome P450, catalyzes the metabolism of a diverse array of xenobiotics. Dimethyl sulfoxide is a commonly used solvent which has been used therapeutically. Dimethyl sulfoxide effects on CYP3A, CYP2E1, CYP2B and NADPH cytochrome P450 reductase expression in rat liver and in primary cultured rat hepatocytes were examined. Dimethyl sulfoxide increased immunodetectable hepatic CYP3A and CYP2E1 levels approximately 2.5 to 3-fold in the absence of any change in the respective mRNA levels. No change in CYP2B or P450 reductase expression was observed, indicating that dimethyl sulfoxide effects were selective. Dimethyl sulfoxide also increased CYP3A protein in rats pretreated with dexamethasone. In primary cultured rat hepatocytes, dimethyl sulfoxide increased CYP3A and CYP2E1 protein without increasing the respective mRNA levels. These results show that dimethyl sulfoxide, at levels relevant to human exposure, enhances CYP3A and CYP2E1 expression by posttranscriptional mechanisms.
Zangar
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RC
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Hernandez
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M
Novak
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RF
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000201:enzymology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
D012333:RNA, Messenger; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D004121:Dimethyl Sulfoxide