RT Journal Article
SR Electronic
T1 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.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 110
OP 115
VO 10
IS 2
A1 T C Orton
A1 G L Parker
YR 1982
UL http://dmd.aspetjournals.org/content/10/2/110.abstract
AB 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 has been studied. Each compound caused dose-dependent increase in liver size and cytochrome P-450 (methylclofenapate = fenofibrate = tibric acid greater than 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 a 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 approximately 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.