Floettmann Jan Eike, Buckett Linda K, Turnbull Andrew V, Smith Tim, Hallberg Carina, Birch Alan, Lees David, Jones Huw B
1Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
Toxicol Pathol. 2013;41(7):941-50. doi: 10.1177/0192623313477753. Epub 2013 Feb 20.
Acyl-coenzyme A: cholesterol O-Acyltransferase (ACAT) and Acyl-coenzyme A: diacylglycerol O-acyltransferase (DGAT) enzymes play important roles in synthesizing neutral lipids, and inhibitors of these enzymes have been investigated as potential treatments for diabetes and other metabolic diseases. Administration of a Acyl-coenzyme A: diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor with very limited cellular selectivity over ACAT resulted in significant adrenocortical degenerative changes in dogs. These changes included macrosteatotic vacuolation associated with adrenocyte cell death in the zonae glomerulosa and fasciculata and minimal to substantial mixed inflammatory cell infiltration and were similar to those described previously for some ACAT inhibitors in dogs. In the mouse, similar but only transient adrenocortical degenerative changes were seen as well as a distinctive nondegenerative reduction in cortical fine vacuolation. In the marmoset, only the distinctive nondegenerative reduction in cortical fine vacuolation was observed, suggesting that the dog, followed by the mouse, is the most sensitive species for cortical degeneration. Biochemical analysis of adrenal cholesterol and cholesteryl ester indicated that the distinctive reduction in cortical fine vacuolation correlated with a significant reduction in cholesteryl ester in the mouse and marmoset, whereas no significant reduction in cholestryl ester, but an increase in free cholesterol was observed in dogs. Administration of a DGAT1 inhibitor with markedly improved selectivity over ACAT to the marmoset and the mouse resulted in no adrenal pathology at exposures sufficient to cause substantial DGAT1 but not ACAT inhibition, thereby implicating ACAT rather than DGAT1 inhibition as the probable cause of the observed adrenal changes. Recognizing that the distinctive nondegenerative reduction in cortical fine vacuolation in the mouse could be used as a histopathological biomarker for an in vivo model of the more severe changes observed in dogs, the mouse has subsequently been used as a model to select DGAT1 inhibitors free of adrenocortical toxicity.
酰基辅酶A：胆固醇O-酰基转移酶（ACAT）和酰基辅酶A：二酰基甘油O-酰基转移酶（DGAT）在中性脂质合成中起重要作用，这些酶的抑制剂已作为糖尿病和其他代谢疾病的潜在治疗方法进行了研究。给予对ACAT细胞选择性非常有限的酰基辅酶A：二酰基甘油O-酰基转移酶1（DGAT1）抑制剂会导致犬肾上腺皮质发生显著退行性变化。这些变化包括与球状带和束状带肾上腺细胞死亡相关的大脂肪变性空泡化，以及轻度至重度混合性炎性细胞浸润，与之前犬类中一些ACAT抑制剂所描述的变化相似。在小鼠中，也观察到了类似但只是短暂的肾上腺皮质退行性变化以及皮质细微空泡化的明显非退行性减少。在狨猴中，仅观察到皮质细微空泡化的明显非退行性减少，这表明犬是对皮质变性最敏感的物种，其次是小鼠。对肾上腺胆固醇和胆固醇酯的生化分析表明，小鼠和狨猴中皮质细微空泡化的明显减少与胆固醇酯的显著减少相关，而在犬中未观察到胆固醇酯的显著减少，但游离胆固醇增加。给予对ACAT选择性显著提高的DGAT1抑制剂给狨猴和小鼠，在足以导致显著DGAT1抑制但不抑制ACAT的暴露剂量下，未出现肾上腺病变，因此表明观察到的肾上腺变化的可能原因是ACAT抑制而非DGAT1抑制。认识到小鼠中皮质细微空泡化的明显非退行性减少可作为犬类中观察到的更严重变化的体内模型的组织病理学生物标志物，随后小鼠被用作筛选无肾上腺皮质毒性的DGAT1抑制剂的模型。
