Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor
Language: 
English
Short Title: 
Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2
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.

Author(s): 
Yang, Jian
Yan, Bingfang
Item Type: 
Journal Article
Publication Title: 
Toxicological Sciences: An Official Journal of the Society of Toxicology
Journal Abbreviation: 
Toxicol. Sci.
Publication Date: 
Jan 2007
Publication Year: 
2007
Pages: 
13-22
Volume: 
95
Issue: 
1
ISSN: 
1096-6080
DOI: 
10.1093/toxsci/kfl120
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 17003103 PMCID: PMC4114574

Turabian/Chicago Citation

Jian Yang and Bingfang Yan. Jan 2007. "Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor." Toxicological Sciences: An Official Journal of the Society of Toxicology 95: 1: 13-22. 10.1093/toxsci/kfl120.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1093/toxsci/kfl120 | issn = 1096-6080 | volume = 95 | pages = 13-22 | last = Yang | first = Jian | coauthors = Yan, Bingfang | title = Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor | journal = Toxicological Sciences: An Official Journal of the Society of Toxicology | date = Jan 2007 | pmid = | pmc = }} </ref>