Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor.
8-Methoxypsoralen (8-MOP) is a prototype photochemotherapeutic agent and used to treat various skin disorders such as psoriasis and cutaneous T-cell lymphoma. Animal studies demonstrate that repeated treatment with 8-MOP markedly increases the capacity of drug metabolism. In this study, we report that 8-MOP is a potent inducer of cytochrome P450 3A4 (CYP3A4) and carboxylesterase 2 (HCE2), two major human enzymes that catalyze oxidative and hydrolytic reactions, respectively. In human primary hepatocytes, 8-MOP markedly induced the expression of CYP3A4 (approximately sixfold) and HCE2 (approximately threefold) and the induction occurred in a concentration-dependent manner (0-50 microM). RNA interference of the expression of the pregnane X receptor (PXR) proportionally decreased the induction. In a reporter assay, 8-MOP stimulated both CYP3A4 and HCE2 promoters, and the stimulation was enhanced by cotransfection of PXR. Several natural variants of PXR differed markedly from the wild-type receptor in responding to 8-MOP. In addition to human PXR (hPXR), 8-MOP activated rat PXR, and the activation was comparable to that of hPXR (EC(50) = approximately 14 microM). PXR is recognized as a master regulator of the genes encoding drug-metabolizing enzymes and transporters. The involvement of PXR in 8-MOP induction suggests that this chemotherapeutic agent causes a broader range of drug-drug interactions, and the differential activation of certain PXR variants suggests that the magnitude of the interactions varies from person to person.
Yang
Jian
J
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Yan
Bingfang
B
D000328:Adult; D000368:Aged; D000818:Animals; D043182:Carboxylesterase / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008156:Luciferases; D008297:Male; D008730:Methoxsalen / Q000633:toxicity*; D017319:Photosensitizing Agents / Q000633:toxicity*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011987:Receptors, Steroid / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D017319:Photosensitizing Agents; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D043182:Carboxylesterase; D008730:Methoxsalen