Elsevier

Biochemical Pharmacology

Volume 55, Issue 4, 15 February 1998, Pages 387-395
Biochemical Pharmacology

Research paper
Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers

https://doi.org/10.1016/S0006-2952(97)00436-XGet rights and content

Abstract

A strong overlap between P-glycoprotein (Pgp) and cytochrome P450 3A (CYP3A) substrates and modulators has been reported. To test the hypothesis that CYP3A and Pgp are coordinately regulated, we examined the effects of known inducers of CYP3A (triacetyloleandomycin, rifampicin, dexamethasone, pregnenolone 16α-carbonitrile) on Pgp expression in rat liver. We also investigated the gender-specific expression of Pgp and compared its response to dexamethasone between male and female rats. In male rats, western blot analyses showed that rifampicin and dexamethasone caused 50% and 5-fold increases in Pgp levels, respectively. RNase protection assays using gene-specific probes for the three Pgp isoforms revealed a 3-fold increase in mdr2 mRNA levels after dexamethasone administration and a 2-fold increase following rifampicin treatment. Triacetyloleandomycin and pregnenolone 16α-carbonitrile had no effect on Pgp expression and mRNA levels. We also observed that the basal level of Pgp was 40% lower in male rats than in females and that mdr2 mRNA levels in male rats were one-half those in females. As opposed to the results in male rats, dexamethasone reduced Pgp expression by approximately 60% and caused a 30% decrease in mdr2 mRNA levels in female rats. Mdr1a was not affected and mdr1b was not detected in female or male rats. We conclude that, at the dosage regimen used, CYP3A and Pgp responses to CYP3A inducers are regulated independently in rat liver. In addition, this study shows that Pgp expression and regulation are gender specific.

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  • Cited by (0)

    This work was supported, in part, by National Institutes of Health Grant GM 26691.

    ∗∗

    We thank Dr. Deanna L. Kroetz, Philip Yook (Department of Biopharmaceutical Sciences), and Dr. Noureddine Lomri (Liver Center Molecular Biology Core Facility) for their assistance with the RNase protection assays and Dr. Jeffrey A. Silverman for critical reading of the manuscript.

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