title: Hypolipidemic activity and toxicity studies of a styrl-hexahydroindolinol, 34-250.
abstract: 34-250 evoked hypocholesterolemic activity in the rat (14, 25, 31, 52, 112 mg/kg, po), dog (10, 20, 40 mg/kg, po), and monkey (30 mg/kg, po). Serum triglycerides were lowered in the rat and dog but not in the monkey. 34-250 increased [14C]acetate incorporation into liver cholesterol, but incorporation of 14C-labeled acetate into serum cholesterol was decreased. Desmosterol or 7-dehydro-cholesterol did not accumulate in serum of the three species, suggesting that inhibition of cholesterol biosynthesis by 34-250 possibly does not occur at a late stage. Normal fecal bile acid excretion was observed in rats, suggesting that cholesterol catabolism probably was not enhanced by 34-250. Compound 34-250-induced hypocholesterolemia may result from inhibition of hepatic release of this sterol into blood. The reversible hepatic lipidosis observed in rats is also possibly related to decreased hepatic transport and/or secretion of triglycerides. 34-250 did not cause a proliferation of hepatic microbodies; the lack of an increase in this fatty acid oxidizing organelle suggests that it may also have had a role in increased hepatic lipidosis. In dogs, a high incidence of severe cataracts with an early onset was induced by 20 and 40 mg/kg, po of 34-250 despite the lack of desmosterol or 7-dehydro-cholesterol in serum. The absence of these late stage intermediates of cholesterol biosynthesis in the serum of a test species does not preclude the occurrence of ocular toxicity.
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D002386:Cataract / Q000139:chemically induced* / Q000473:pathology; D002428:Cebus; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007211:Indoles / Q000633:toxicity*; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D007211:Indoles; D008074:Lipoproteins; D014280:Triglycerides; C038511:bis(4-(3,4-dimethoxystyryl)hexahydro-4-indolinol); D002784:Cholesterol