title: 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 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.
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002144:Callithrix; D002994:Clofibrate / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction / Q000187:drug effects; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D006900:Hydroxylation; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007850:Lauric Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase
chemical_list: D000960:Hypolipidemic Agents; D007850:Lauric Acids; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; C006012:fenofibric acid; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D009245:NADH Dehydrogenase; D002994:Clofibrate; D011345:Fenofibrate