Coinduction of MDR-1 multidrug-resistance and cytochrome P-450 genes in rat liver by xenobiotics.
The levels of mRNA for multidrug-resistance (MDR-1) and selective cytochrome P-450 genes were determined in adult rat liver following administration of various natural and synthetic xenobiotics. MDR-1 (also known as PGY1) was induced following administration of aflatoxin B1, 2-(acetylamino)fluorene (AAF), N-hydroxy-2-(acetylamino)fluorene, isosafrole, phenothiazine, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but not after phenobarbital or 7-hydroxy-2-(acetylamino)fluorene treatment. Cytochrome P-450 isoform d was induced by TCDD, isosafrole, phenothiazine, and AAF, while cytochrome P-450 isoform b was induced by phenobarbital, and to a lesser extent by isosafrole. These observations suggest that both MDR and cytochrome P-450 gene families are evolutionarily selected by the capacity of various xenobiotics to induce their own detoxification either through metabolism to hydrophilic derivatives by the cytochrome P-450 system or direct excretion from the cell by the MDR gene family. Furthermore, the data indicate that induction of selective members of the MDR and the cytochrome P-450 gene families may depend on overlapping regulatory elements.
Burt
R K
RK
Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD 20892.
Thorgeirsson
S S
SS
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D051379:Mice; D005810:Multigene Family; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000502:physiology; D015262:Xenobiotics / Q000494:pharmacology*
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene