Regulation of Hepatic CYP3A4 by 3‐Methylcholanthrene in Humanized PXR‐CAR‐CYP3A4/3A7 Mice

Polycyclic aromatic hydrocarbons (PAHs) are a broad class of priority environmental pollutants. These chemicals exert a wide array of health effects through activation of the aryl hydrocarbon receptor (AHR). A well‐documented response to AHR activation is the pronounced induction of cytochrome P450 1A1 (CYP1A1), a drug‐metabolizing enzyme involved in phase I drug biotransformation. Interestingly, less is known about the regulation of human cytochrome P450 3A4 (CYP3A4) by PAHs. Alterations of CYP3A4 expression and activity are of tremendous importance to drug metabolism, since this enzyme's abundance and central role in drug metabolism rank it among the most important human cytochromes P450. As such, CYP3A4 is a common target for drug interactions. Our laboratory has previously shown that treatment of male C57BL/6 mice with 3‐methylcholanthrene (MC), a model PAH, suppressed the activity and expression of hepatic Cyp3a11, the mouse counterpart of human CYP3A4. Controversially, studies in primary human hepatocytes and liver‐derived continuous cell lines report both inductive and suppressive effects of PAHs on human CYP3A4 expression. The current study used MC to study the effects of PAHs on CYP3A4 activity and expression in a novel humanized PXR‐CAR‐CYP3A4/3A7 mouse model [Hasegawa et al. Mol Pharmacol 80: 518–28, 2011]. Adult male and female mice were treated by intraperitoneal injection with MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours after injection. Livers were subsequently harvested for analysis of CYP3A4 catalytic activity, protein expression and mRNA expression. Marked induction of mouse hepatic Cyp1a1 expression by MC at both 24 and 72 hours was confirmed as a positive control response. Basal hepatic CYP3A4 expression at the catalytic activity, protein, and mRNA levels was significantly higher in female vs. male mice, a sexual dimorphism not reported in the original published characterization of this humanized mouse strain. A similar sex difference in hepatic CYP3A4 expression was documented previously in a CYP3A4/3A7‐transgenic mouse line [Cheung et al. J Pharmacol Exp Ther 316: 1328–34, 2006]. Further, MC decreased CYP3A4 activity and expression in female mice 72 hours after injection. Despite much lower basal hepatic expression of CYP3A4 compared to females, similar trends for CYP3A4 suppression by MC were observed in male mice; these trends did not achieve statistical significance. Our results suggest that this humanized mouse model will be useful for further investigations of the underlying mechanisms and functional consequences of hepatic CYP3A4 suppression by PAHs in an in vivo system. Support or Funding Information Canadian Institutes of Health Research

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