Morphological and enzymatic alterations in the rat liver caused by administration of a hypocholesterolemic agent AT-308 and its related compounds

The administration of a hypocholesterolemic agent, 3-4-(1-ethoxycarbonyl-1-methylethoxy)phenyl]-5-(3-pyridyl)-1, 2, 4-oxadiazole (AT-308), to rats induced hepatomegaly accompanying a significant proliferation of microbodies. AT-308 and some related compounds were given to rats to investigate the relationship between chemical structures of the test compounds and their several biological effects including hypocholesterolemic effect, proliferation of hepatic microbodies, induction of liver catalase activity and drug-metabolizing enzyme activity as manifested by pentobarbital sleeping time. The results obtained are as follows. First the administration of AT-308 or clofibrate to rats fed a basal or high cholesterol diet produced a significant increase in the number of hepatic microbodies. especially of anucleoid type. The administration of 3-4-(2-diethyl-aminoethoxy)phenyl]-5-(3-pyridyl)-1, 2, 4-oxadiazole (AT-293) induced a slight increase in the number of hepatic microbodies, and 3, 5-di-(3-pyridyl)-1, 2, 4-oxadiazole (AT-232) did not produce such an increase at all. Second, the liver catalase activity increased in the AT-308- and clofibrate-treated groups, but the increase of the latter was less prominent than that of the former. Third, the administration of AT-308 or clofibrate. but not of AT-293 or AT-232, shortened the duration of pentobarbital anesthesia. These results suggest that the proliferation of hepatic microbodies with AT-308 administration may be ascribable to a clofibrate-like side chain in the molecule of AT-308 and not to its 1, 2, 4-oxadiazole moiety.