Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor.
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Yang J, Yan B
Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor.
Toxicol Sci. 2007 Jan;95(1):13-22. Epub 2006 Sep 26.
- PubMed ID
- 17003103 [ View in PubMed]
- Abstract
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.