COMPARISON OF EFFECTS OF XENOBIOTICS ON EXTRAHEPATIC AND HEPATIC-MICROSOMAL DRUG-METABOLIZING-ENZYMES IN MICE

The content of microsomal protein is the same in both kidneys and smal l intestine, corresponding to 57% of the control value expressed as 10 0% in the untreated liver. The contents of P450 and cytochrome b(5), a nd the activity of NADPH-cytochrome c reductase in the kidney were hig her than those in the small intestine, which were 17%, 22% and 41% of controls, respectively, in the former and 5%, 11% and 22% of controls in the latter. As compared with similar measurements made in the liver , the activities of substrate-metabolizing enzymes in these extrahepat ic were very low. The activities of renal aniline hydroxylase, aminopy rine N-demethylase, 7-ethoxycoumarin O-deethylase, 7-methoxycoumarin O -demethylase and benzo(a)pyrene hydroxylase were 6%, 5%, 3%, 0.6% and 0.2% of controls, respectively. The activities of these enzymes in the small intestine were lower than those in the kidney or below the limi ts of detection. These results suggested that isoforms or their conten ts of P450 responsible for these substrate biotransformations are diff erent among liver, kidneys and small intestine. Meantime, this study s howed similar significant inductions by phenobarbital and rifampin of small intestinal and hepatic microsomal drug-metabolizing enzymes. In contrast, neither phenobarbital nor rifampin was capable of increasing renal microsomal enzymes, with the exception of benzo(a)pyrene hydrox ylase which was induced by rifampin. These findings indicated that bot h liver and small intestine, but not kidneys contain the same phenobar bital- and rifampin-inducible P450 isoforms, cytochrome b(5) and NADPH -cytochrome c reductase. In addition, CCl4 could be bioactivated by CY P2E1 to free radicals in the kidney which caused destruction of micros omal enzymes. In mice pretreated with phenobarbital, CCl4 also attenua ted the increase in content of P450 in the small intestine, which appe ared to be a result of induction by phenobarbital of CYP2E1.