Biomaterial Database

Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. 1998

L Salphati, and L Z Benet

Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.

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.

UI	MeSH Term	Description	Entries
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008297	Male		Males
D010089	Oxidoreductases, N-Demethylating		N-Demethylase,N-Demethylases,Oxidoreductases, N Demethylating,Demethylating Oxidoreductases, N,N Demethylase,N Demethylases,N Demethylating Oxidoreductases,N-Demethylating Oxidoreductases
D011285	Pregnenolone Carbonitrile	A catatoxic steroid and microsomal enzyme inducer having significant effects on the induction of cytochrome P450. It has also demonstrated the potential for protective capability against acetaminophen-induced liver damage.	PCN,Pregnenolone 16 alpha-Carbonitrile,Pregnenolone Carbonitrile, (3 beta)-Isomer,Pregnenolone Carbonitrile, (3 beta,16 beta)-Isomer,16 alpha-Carbonitrile, Pregnenolone,Carbonitrile, Pregnenolone,Pregnenolone 16 alpha Carbonitrile
D003577	Cytochrome P-450 Enzyme System	A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism.	Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D003907	Dexamethasone	An anti-inflammatory 9-fluoro-glucocorticoid.	Hexadecadrol,Decaject,Decaject-L.A.,Decameth,Decaspray,Dexasone,Dexpak,Hexadrol,Maxidex,Methylfluorprednisolone,Millicorten,Oradexon,Decaject L.A.
D004790	Enzyme Induction	An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis.	Induction, Enzyme
D005260	Female		Females
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D001189	Aryl Hydrocarbon Hydroxylases	A large group of cytochrome P-450 (heme-thiolate) monooxygenases that complex with NAD(P)H-FLAVIN OXIDOREDUCTASE in numerous mixed-function oxidations of aromatic compounds. They catalyze hydroxylation of a broad spectrum of substrates and are important in the metabolism of steroids, drugs, and toxins such as PHENOBARBITAL, carcinogens, and insecticides.	Microsomal Monooxygenases,Xenobiotic Monooxygenases,Hydroxylases, Aryl Hydrocarbon,Monooxygenases, Microsomal,Monooxygenases, Xenobiotic