Received for publication September 24, 2007.
Revised November 16, 2007.
Accepted for publication November 20, 2007.

Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice

Abstract

Abstract: Analysis of the developmental and sexual expression of cytochrome P450 (CYP) drug-metabolizing enzymes is impeded by multiple and varied external factors that influence its regulation. In the present study, a CYP2D6/CYP3A4-double transgenic (Tg-CYP2D6/CYP3A4) mouse model was employed to investigate hepatic CYP2D6 and CYP3A4 ontogeny and sexual dimorphism. Both age and sex have considerable effects on hepatic CYP3A4 protein expression in 3- to 8-week-old transgenic mice, whereas neither factor alters CYP2D6 content. Constitutive CYP2D6 expression resulted in 2- to 3-fold higher dextromethorphan O-demethylase activity in Tg-CYP2D6/CYP3A4 mouse liver microsomes when compared to wild-type mice. In contrast, expression of CYP3A4 in transgenic mouse livers did not increase dextromethorphan N-demethylase and midazolam 1'-hydroxylase activities. Pretreatment with pregnenolone 16alpha-carbonitrile (PCN) and 1,4-bis-2-(3, 5-dichloropyridyloxy)-benzene (TCPOBOP) elevated CYP3A4 expression in double transgenic mice. Interestingly, induction of hepatic CYP3A4 was greater in females than age- and treatment-matched males. Consequently, the increase in midazolam 1’-hydroxylase activity was markedly higher in 8-week-old female mice than in corresponding males (8-fold vs. 6-fold for PCN treatment and 6-fold vs. 5-fold for TCPOBOP). Furthermore, increases in testosterone 6beta-hydroxylase activity after CYP3A induction were relatively lower when compared to those in midazolam 1’-hydroxlyation for age-, sex- and treatment-matched mice. The difference in CYP3A4 expression and induction between male and female mice suggests that women may be more susceptible to CYP3A4-mediated drug-drug interactions, and the extent of drug-drug interactions could be substrate dependent.

Key words: CYP expression, CYP gene regulation, CYP induction, CYP2D, CYP3A, drug-drug interactions, human CYP enzymes, transgenic models

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