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First published on October 4, 2006; DOI: 10.1124/dmd.106.011270

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Received for publication June 12, 2006.
Revised September 27, 2006.
Accepted for publication September 29, 2006.

Gender dictates the nuclear receptor mediated regulation of CYP3A44

Sayeepriyadarshini Anakk 1, Wendong Huang 1, Jeffrey L Staudinger 2, Kheng Tan 3, Timothy J Cole 3, David D Moore 1, Henry W. Strobel 4*

1 Baylor College of Medicine 2 University of Kansas 3 Monash University 4 The Univ. of Texas Medical School at Houston

* Address correspondence to: E-mail: henry.w.strobel{at}uth.tmc.edu

Abstract

The cytochromes P4503A are broad spectrum drug metabolizing enzymes that are collectively responsible for more than 50% of xenobiotic metabolism. Unlike other CYP3As, murine CYP3A44 is expressed predominantly in the female liver, with much lower levels in male livers and no detectable expression in brain or kidney in either gender. In this study, we examined the role of nuclear hormone receptors in the regulation of Cyp3a44 gene expression. Interestingly, we observed differential effects of Pregnane-X-Receptor (PXR), and Constitutive Androstane Receptor (CAR) mediated activation of Cyp3a44 gene expression, which was gender-specific. For instance, activation of PXR by Pregnenolone-16{alpha}-carbonitrile, (PCN) and Dexamethasone, (DEX) induced CYP3A44 mRNA levels in a PXR-dependent fashion in male mice, whereas no induction was detected in female mice. In contrast, PCN and DEX down-regulated CYP3A44 expression in female PXR null animals. Similar to PXR, CAR activation also showed a male-specific induction with no effect on CYP3A44 levels in female. When PXR knockout mice were challenged with the CAR activator Phenobarbital, a significant up regulation of male CYP3A44 levels was observed while levels in females remained unchanged. We conclude that gender has a critical impact on PXR and CAR mediated effects of CYP3A44 expression.


Key words: CAR, cytochrome P450 regulation, PXR, sexual dimorphism


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W. Bhadhprasit, T. Sakuma, N. Hatakeyama, M. Fuwa, K. Kitajima, and N. Nemoto
Involvement of Glucocorticoid Receptor and Pregnane X Receptor in the Regulation of Mouse CYP3A44 Female-Predominant Expression by Glucocorticoid Hormone
Drug Metab. Dispos., October 1, 2007; 35(10): 1880 - 1885.
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