Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice.
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 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 versus 6-fold for PCN treatment and 6-fold versus 5-fold for TCPOBOP). Furthermore, increases in testosterone 6beta-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.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Melanie A
MA
Felmlee
Hoi-Kei
HK
Lon
Frank J
FJ
Gonzalez
Ai-Ming
AM
Yu
D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008861:Microsomes / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism; D008565:Membrane Proteins
D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003915:Dextromethorphan; D008874:Midazolam; D011285:Pregnenolone Carbonitrile; D011725:Pyridines; D013739:Testosterone; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; C510163:CYP3A4 protein, human; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins