THE EFFECT OF HYPOLIPIDEMIC AGENTS ON THE HEPATIC-MICROSOMAL DRUG-METABOLIZING ENZYME-SYSTEM OF THE RAT - INDUCTION OF CYTOCHROME(S)-P-450 WITH SPECIFICITY TOWARD TERMINAL HYDROXYLATION OF LAURIC ACID

Abstract

The effect of chronic dietary administration of the hypolipidemic agents clofibrate, methylclofenapate, fenofibrate and tibric acid, on the hepatic drug-metabolizing enzyme system of the albino rat was studied. Each compound caused dose-dependent increase in liver size and cytochrome P-450 (methylclofenapate = fenofibrate = tibric acid > clofibrate). NADPH-cytochrome c reductase activity was increased only after clofibrate and methylclofenapate treatment. There was no overall increase in the metabolism of a number of commonly used model substrates in parallel with the cytochrome P-450 induction. Aminopyrine and ethoxyresorufin dealkylation, biphenyl 4-hydroxylation, testosterone 16.alpha.-hydroxylation and o-aminophenol and chloramphenicol glucuronidation showed no change or inhibition, whereas ethoxycoumarin and phenacetin dealkylation and testosterone 6.beta.-hydroxylation were increased (only up to 2-fold). Using clofibrate as representative of this class of pharmacological agent, the enzymatic changes were essentially reversed within 6 days after removal of drug from the diet. Clofibrate administration also increased liver size and, to a lesser extent, hepatic cytochrome P-450 content in the albino (CD-1) mouse but had no effect in the marmoset monkey. In the rat, clofibrate administration specifically increased the hepatic microsomal .omega.-hydroxylation of lauric acid .apprx. 28-fold, which contrasted with the specific increase in (.omega.-1)-hydroxylation caused by phenobarbital administration. The specific increase in microsomal cytochrome P-450-mediated .omega.-oxidation of a medium length, straight chain, saturated fatty acid is similar to the documented increase in peroxisomal and mitochondrial fatty acid .beta.-oxidation caused by administration of hypolipidemic agents.