Reindel J F, Dominick M A, Bocan T M, Gough A W, McGuire E J
Department of Pathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
Toxicol Pathol. 1994 Sep-Oct;22(5):510-8. doi: 10.1177/019262339402200505.
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.
将酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂PD 132301-2以25、50、100和200mg/kg的剂量口服给予食蟹猴2周，以评估潜在的亚急性毒性。软便和腹泻的偶发事件发生率从100mg/kg至200mg/kg有所增加。经治疗的猴子肾上腺皮质细胞的组织病理学改变包括剂量相关的细胞质细微空泡化减少以及在束状带和网状带中最明显的细胞质嗜酸性增加。在50、100和200mg/kg时，在束状带外层出现了一个狭窄的、不连续的细胞毒性皮质细胞变性区。皮质细胞细微空泡化减少在超微结构上与细胞内脂质空泡的大小和数量减少相关，在生化方面与肾上腺总胆固醇（从对照的56%降至13%）和胆固醇酯（从对照的51%降至3%）浓度的剂量相关降低相关。在所有剂量下，束状带皮质细胞中观察到的其他超微结构变化是滑面内质网和大小不一的自噬空泡均明显增加。所有剂量下一些雌性动物的卵巢黄体黄体细胞粗空泡化增加、细胞变性灶、胆固醇裂隙数量增加以及单核细胞轻度浸润。所有经治疗的猴子皮脂腺均萎缩，主要原因是分化的泡沫细胞大小和数量减少。皮脂腺储备细胞肥大且增生。该研究的毒性数据表明，25-200mg/kg的PD 132301-2靶向肾上腺、卵巢和皮肤附属器中富含胆固醇的细胞。
