Hypolipidemic activity and toxicity studies of a styrl-hexahydroindolinol, 34-250.

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.
AuthorsR E Bagdon, R G Engstrom, L A Kelly, H A Hartman, R L Robison, G E Visscher
JournalToxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 69 Issue 1 Pg. 12-28 (Jun 15 1983) ISSN: 0041-008X [Print] UNITED STATES
PMID6857683 (Publication Type: Journal Article)
Chemical References
  • Anticholesteremic Agents
  • Indoles
  • Lipoproteins
  • Triglycerides
  • bis(4-(3,4-dimethoxystyryl)hexahydro-4-indolinol)
  • Cholesterol
  • Animals
  • Anticholesteremic Agents (toxicity)
  • Biological Transport (drug effects)
  • Cataract (chemically induced, pathology)
  • Cebus
  • Cholesterol (biosynthesis, blood)
  • Dogs
  • Dose-Response Relationship, Drug
  • Female
  • Indoles (toxicity)
  • Lipoproteins (blood)
  • Liver (drug effects, metabolism, ultrastructure)
  • Male
  • Rats
  • Rats, Inbred Strains
  • Species Specificity
  • Triglycerides (secretion)

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