Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.

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Murayama N, van Beuningen R, Suemizu H, Guillouzo CG, Shibata N, Yajima K, Utoh M, Shimizu M, Chesne C, Nakamura M, Guengerich FP, Houtman R, Yamazaki H

Thalidomide increases human hepatic cytochrome P450 3A enzymes by direct activation of the pregnane X receptor.

Chem Res Toxicol. 2014 Feb 17;27(2):304-308. doi: 10.1021/tx4004374. Epub 2014 Feb 5.

PubMed ID

24460184 [ View in PubMed

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Abstract

Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. ( ( 2013 ) Chem. Res. Toxicol. 26 , 486 - 489 ) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pretreatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting the activation of upstream transcription factors involved in detoxication, e.g., the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of coregulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 coregulator-derived nuclear receptor-interaction motifs and coregulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5-hydroxythalidomide displayed significant modulation of coregulator interaction with PXR and CAR ligand-binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Thalidomide	Cytochrome P450 2B6	Protein	Humans	No	Substrate Inducer	Details
Thalidomide	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Thalidomide	Approved Investigational Withdrawn	CYP2B6	1555	upregulated	Thalidomide results in increased expression of CYP2B6 mRNA	19q13.2
Thalidomide	Approved Investigational Withdrawn	CYP3A4	1576	upregulated	Thalidomide results in increased expression of CYP3A4 mRNA	7q22.1