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ToxSci Advance Access published online on September 26, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl120
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 1, 2006
Accepted September 18, 2006

Biotransformation and Toxicokinetics

Photochemotherapeutic agent 8-methoxypsoralen induces Cytochrome P450 3A4 and Carboxylesterase HCE2: Evidence on an Involvement of the Pregnane X Receptor

Jian Yang 1 and Bingfang Yan 1 *

1 Department of Biomedical Sciences, University of Rhode Island, Kingston, RI 02881

* To whom correspondence should be addressed.
Bingfang Yan, E-mail: byan{at}uri.edu


  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 (~6 fold) and HCE2 (~3 fold) and the induction occurred in a concentration-dependent manner (0-50 µM). 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 co-transfection of PXR. Several natural variants of PXR differed markedly from the wild-type receptor in responding to 8-MOP. In addition to human PXR, 8-MOP activated rat PXR, and the activation was comparable to that of human PXR (EC50 = ~14 µM). 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.

Keywords: Psoralen; 8-methoxypsoralen; photochemotherapy; Cytochrome P450 3A4; carboxylesterase HCE2; PXR.
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[Abstract] [Full Text] [PDF]


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