Abstract
Analysis of the developmental and sexual expression of cytochrome P450 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 compared with 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 16α-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 versus 6-fold for PCN treatment and 6-fold versus 5-fold for TCPOBOP). Furthermore, increases in testosterone 6β-hydroxylase activity after CYP3A induction were relatively lower compared with those in midazolam 1′-hydroxylation 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.
Footnotes
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A.-M.Y. is grateful for support from the Kapoor Foundation. M.A.F. is supported by a Pfizer Graduate Student Fellowship.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018838.
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ABBREVIATIONS: P450, cytochrome P450; DDI, drug-drug interaction; DXM, dextromethorphan; DXO, dextrorphan; MEM, 3-methoxymorphinan; MDZ, midazolam; TEST, testosterone; PCN, pregnenolone 16α-carbonitrile; TCPOBOP, 1,4-bis-2-(3,5-dichloropyridyloxy)-benzene; PCR, polymerase chain reaction; mEH, microsomal epoxide hydrolase; bp, base pairs; HPLC, high-performance liquid chromatography.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Received September 12, 2007.
- Accepted November 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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