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ToxSci Advance Access originally published online on September 26, 2006
Toxicological Sciences 2007 95(1):13-22; 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

Photochemotherapeutic Agent 8-Methoxypsoralen Induces Cytochrome P450 3A4 and Carboxylesterase HCE2: Evidence on an Involvement of the Pregnane X Receptor

Jian Yang*,{dagger} and Bingfang Yan*,1

* Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881 {dagger} Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China

1 To whom correspondence should be addressed. Fax: (401) 874-5787. E-mail: byan{at}uri.edu.

Received August 1, 2006; accepted September 18, 2006


  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 (0–50µM). 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 (EC50 = ~14µM). 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.

Key Words: psoralen; 8-methoxypsoralen; photochemotherapy; cytochrome P450 3A4; carboxylesterase HCE2; PXR.


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