Coinduction of MDR-1 Multidrug-Resistance and Cytochrome P-450 Genes in Rat Liver by Xenobiotics

Abstract

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 B₁2-(acetylamino)fluorene (AAF), N-hydroxy-2-(accetylamino)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 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. [J Natl Cancer Inst 1988;80:1383–1386]