title: Effects of compound X, a novel potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase, on the adrenal gland of rats.
abstract: To investigate the adrenal toxicity of a novel inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase, compound X (CX), histopathological examinations, fat staining, adrenal cholesterol measurement, blood biochemistry, plasma corticosterone and ACTH measurement, ACTH-stimulation assay, and adrenal gene-expression analyses were done in rats in repeated-dose studies (experiment 1: 0, 3, 10, 30 and 150mg/kg for 4, 8, 15 and 28 days; experiment 2: 0, 3, 10,30 and 150mg/kg for 28 days; experiment 3: 0, 10, 30, 100 and 300mg/kg for 28 days). CX induced morphologic changes such as vacuolation and hypertrophy in the zona fasciculata (ZF) at ≥10mg/kg, and eosinophilic changes in the ZF at 150mg/kg. Vacuolation decreased in a dose-dependent manner and was replaced by eosinophilic changes. Inflammatory and fibrous changes were observed at ≥30mg/kg. These changes were expressed at early stages of dosing and were not exacerbated by extension of the administration period. Oil-red-O/Filipin staining showed depletion of cholesterol ester in dose-dependent manner and enabled adrenal cholesterol measurement. Filipin staining also revealed vacuoles to be composed of cholesterol esters. No significant changes were observed during the dosing period of CX for plasma corticosterone and ACTH levels. Gene-expression analyses showed up-regulation of Star and Abca1 mRNA levels at 300mg/kg. In conclusion, CX induced adrenal toxicity, but CX did not influence adrenocortical functions, and exacerbation of adrenal toxicities by extension of the administration period was not observed. Up-regulation of genes related to the transport of FC, such as Star and Abca1, were observed in CX groups, and these genes may be involved in the maintenance of adrenal structure and function in rats given CX.
authors: Toxicology Department, Fuji Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 332-1 Ohnoshinden, Fuji, Shizuoka 417-8650, Japan. Electronic address: j-nisimr@kowa.co.jp.
authors: Jihei
authors: J
authors: Nishimura
authors: Kozo
authors: K
authors: Ohmichi
authors: Eiji
authors: E
authors: Wato
authors: Tsuyoshi
authors: T
authors: Saito
authors: Kazumi
authors: K
authors: Takashima
authors: Takeshi
authors: T
authors: Tanaka
authors: Yuusuke
authors: Y
authors: Hiwatashi
authors: Keita
authors: K
authors: Kobayashi
authors: Takuya
authors: T
authors: Tsujimoto
authors: Masato
authors: M
authors: Asahiyama
authors: Keisuke
authors: K
authors: Itagaki
authors: Sohei
authors: S
authors: Tanabe
authors: Naoki
authors: N
authors: Kato
authors: Yukinori
authors: Y
authors: Amano
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000097:blood; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D064286:ATP Binding Cassette Transporter 1; D003345:Corticosterone; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D002785:Sterol O-Acyltransferase; D000098682:Steroidogenic Acute Regulatory Protein; C577834:Abca1 protein, rat
keywords: ACAT; Abca1; Acyl-coenzyme A:cholesterol O-acyltransferase; Adrenal toxicity; Cholesterol ester; Free-cholesterol; Rat; Star