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Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 1998 Feb 15; Vol. 55 (4), pp. 387-95. - Publication Year :
- 1998
-
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 16alpha-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 16alpha-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.
- Subjects :
- ATP-Binding Cassette Transporters genetics
ATP-Binding Cassette Transporters metabolism
Animals
Cytochrome P-450 CYP3A
Dexamethasone pharmacology
Enzyme Induction drug effects
Female
Gene Expression drug effects
Male
Pregnenolone Carbonitrile pharmacology
RNA, Messenger genetics
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Rifampin pharmacology
Sex Characteristics
Troleandomycin pharmacology
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 Enzyme System biosynthesis
Liver drug effects
Liver metabolism
Oxidoreductases, N-Demethylating biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 55
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9514072
- Full Text :
- https://doi.org/10.1016/s0006-2952(97)00436-x