Difference between Normal and WHHL Rabbits in Susceptibility to the Adrenal Toxicity of an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, FR145237

• Published in: Toxicology and applied pharmacology Vol. 140; no. 2; pp. 387 - 392
• Main Authors: Matsuo, Masahiko, Hashimoto, Masaharu, Suzuki, Jyunya, Iwanami, Kohki, Tomoi, Masaaki, Shimomura, Kyoichi
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.10.1996; Elsevier
• Subjects: Adrenal Cortex - drug effects; Adrenal Cortex - metabolism; Adrenal Cortex - pathology; Adrenal Cortex Diseases - enzymology; Adrenal Cortex Diseases - genetics; Adrenal Cortex Diseases - pathology; Animals; Benzofurans - blood; Benzofurans - toxicity; Biological and medical sciences; Disease Susceptibility; Drug toxicity and drugs side effects treatment; Hyperlipidemias - enzymology; Hyperlipidemias - genetics; Hyperlipidemias - pathology; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Pharmacology. Drug treatments; Phenylurea Compounds - blood; Phenylurea Compounds - toxicity; Rabbits; Receptors, LDL - deficiency; Species Specificity; Sterol O-Acyltransferase - antagonists & inhibitors; Acyltransferases; Animal model; Adrenal glands; Enzyme; Toxicity; Transferases; Deficiency; Enzyme inhibitor; Rabbit; Lagomorpha; Genetic disease; Lipoprotein LDL; Vertebrata; Mammalia; Animal; Hyperlipemia; Pharmacokinetics; Antilipemic agent; Biological receptor; Sterol O-acyltransferase
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1996.0235

The adrenal toxicity of an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, FR145237, was investigated using Japanese White (normal) and low density lipoprotein (LDL) receptor deficient Watanabe heritable hyperlipidemic (WHHL) rabbits. In the normal rabbits, severe necrosis of the cells in the zona fasciculata and reticularis was observed 24 hr after intravenous injection of 3.2 mg/kg of FR145237, whereas no morphological changes could be found in the adrenal cells of the WHHL rabbits in spite of a higher plasma concentration of the drug. Since most of the FR145237 (87%) in the plasma of the WHHL rabbits was recovered in the LDL fraction 1 hr after intravenous injection of the drug (3.2 mg/kg), it was hypothesized that the delivery of the drug to the adrenal cells may be limited by the LDL receptor deficiency. However, the concentration of FR145237 in the adrenal gland of the WHHL rabbits (13.3 μg/g) was identical to that in the normal rabbits (13.6 μg/g). These results suggest that the susceptibility of the adrenal cells of the WHHL rabbits to the toxicity of FR145237 truly differs from that of normal rabbits, and that the WHHL rabbit may be a useful animal model for the investigation of the mechanisms of the adrenal toxicity of ACAT inhibitors.