Differential drug-induced mRNA expression of human CYP3A4 compared to CYP3A5, CYP3A7 and CYP3A43.
Drug-mediated regulation of mRNA expression of all members of the cytochrome P450 3A (CYP3A) subfamily has been measured by reverse transcription-polymerase chain reaction (RT-PCR) in the human hepatocellular carcinoma cell line, HepG2. Transcriptional regulation was proved by inhibition of induction with actinomycin D. Besides the positive control dexamethasone, the H(+)/K(+)-ATPase inhibitors omeprazole, lansoprazole, pantoprazole, and rabeprazole, and the herbal antidepressant St. John's wort (Hypericum extract) were studied. All CYP3A mRNAs were induced by dexamethasone. CYP3A4 was the only CYP3A isoform that was induced by all of the four benzimidazole derivatives, while CYP3A5, CYP3A7, and CYP3A43 were unaffected or even slightly downregulated by these drugs. St. John's wort also increased CYP3A4 mRNA exclusively, leaving CYP3A5 and CYP3A43 unaffected, whereas CYP3A7 was decreased. Depending on the inducer, expression of CYP3A4 is differently regulated from CYP3A5, CYP3A7, and CYP3A43.
Krusekopf
Solveigh
S
Institute of Clinical Pharmacology, Charité, Humboldt University of Berlin, Schumannstr. 20/21, D-10098, Berlin, Germany. Solveigh.Krusekopf@charite.de
Roots
Ivar
I
Kleeberg
Ullrich
U
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D064747:Lansoprazole; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077402:Pantoprazole; D028321:Plant Preparations / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D064750:Rabeprazole; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D028321:Plant Preparations; D012333:RNA, Messenger; D013454:Sulfoxides; D064747:Lansoprazole; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D000077402:Pantoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C422408:CYP3A43 protein, human; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole