Toxicologic effects of a novel acyl-CoA:cholesterol acyltransferase inhibitor in cynomolgus monkeys.
PD 132301-2, an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, was administered orally to cynomolgus monkeys for 2 wk at doses of 25, 50, 100, and 200 mg/kg to assess potential subacute toxicity. Sporadic episodes of soft feces and diarrhea increased in incidence from 100 to 200 mg/kg. Histopathologic alterations in adrenocortical cells of treated monkeys consisted of a dose-related decrease in cytoplasmic fine vacuolation and an increase in cytoplasmic eosinophilia most conspicuous in the zona fasciculata and reticularis. At 50, 100, and 200 mg/kg, a narrow discontinuous zone of cytotoxic cortical cell degeneration occurred in the outer zona fasciculata. Decreased fine vacuolation of cortical cells correlated ultrastructurally with reduced size and number of intracellular lipid vacuoles and biochemically with a dose-related decrease in adrenal total cholesterol (from 56 to 13% of control) and cholesteryl ester (from 51 to 3% of control) concentrations. Other ultrastructural changes noted in zona fasciculata cortical cells at all doses were an apparent increase in both smooth endoplasmic reticulum and variably sized autophagic vacuoles. Ovarian corpora lutea in some females at all doses had increased coarse vacuolation of luteal cells, foci of cellular degeneration, increased numbers of cholesterol clefts, and slight infiltrates of mononuclear cells. Sebaceous glands were atrophic in all treated monkeys due largely to a reduction in size and number of differentiated foam cells. Sebaceous gland reserve cells were hypertrophic and hyperplastic. Toxicity data from this study indicated that PD 132301-2 at 25-200 mg/kg targeted cholesterol-rich cells of the adrenals, ovaries, and skin adnexa.
Reindel
J F
JF
Department of Pathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
Dominick
M A
MA
Bocan
T M
TM
Gough
A W
AW
McGuire
E J
EJ
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D008074:Lipoproteins / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D010053:Ovary / Q000187:drug effects; D010671:Phenylurea Compounds / Q000633:toxicity*; D012627:Sebaceous Glands / Q000187:drug effects; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
D008074:Lipoproteins; D010671:Phenylurea Compounds; D014280:Triglycerides; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C079534:N-(2,6-bis(1-methylethyl)phenyl)-N'-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride