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

Melanie A. Felmlee, Hoi Kei Lon, Frank J. Gonzalez, Aiming Yu

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)435-441
Number of pages7
JournalDrug Metabolism and Disposition
Volume36
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2D6
Cytochrome P-450 Enzyme System
Transgenic Mice
Midazolam
Mixed Function Oxygenases
Pregnenolone Carbonitrile
Drug interactions
Liver
Drug Interactions
N Demethylating Oxidoreductases
Pharmaceutical Preparations
Dextromethorphan
Hydroxylation
Liver Microsomes
Sex Characteristics
Testosterone
Therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice. / Felmlee, Melanie A.; Lon, Hoi Kei; Gonzalez, Frank J.; Yu, Aiming.

In: Drug Metabolism and Disposition, Vol. 36, No. 2, 02.2008, p. 435-441.

Research output: Contribution to journalArticle

Felmlee, Melanie A. ; Lon, Hoi Kei ; Gonzalez, Frank J. ; Yu, Aiming. / Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice. In: Drug Metabolism and Disposition. 2008 ; Vol. 36, No. 2. pp. 435-441.
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