Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits.
Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits.
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发表时间：
1989-02
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通讯作者：
D. Kornbrust;J. MacDonald;C. Peter;D. M. Duchai;R. Stubbs;J. Germershausen;A. Alberts
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作者：
D. Kornbrust;J. MacDonald;C. Peter;D. M. Duchai;R. Stubbs;J. Germershausen;A. Alberts
洛伐他汀是一种胆固醇生物合成限速酶HMG-CoA还原酶的特异性抑制剂，已被证明在降低动物和人类血清胆固醇方面非常有效，因此代表了治疗和预防心血管疾病的一种有希望的方法。在洛伐他汀的临床前安全性评估中，在亚急性研究中发现，狗、大鼠和小鼠耐受的口服剂量对家兔是致命的。家兔死后表现为小叶中心肝坏死，常伴有肾小管坏死，偶尔伴有胆囊坏死。肝脏病变与血清天冬氨酸和丙氨酸转氨酶活性升高高达300倍有关，而肾脏病变导致血清尿素氮和肌酐的积累。在器官受损之前，食物摄入量逐渐减少，体重下降。洛伐他汀引起的所有组织病理学和血清生化变化完全可以通过联合给药甲羟戊酸（抑制HMG-CoA还原酶的产物）来预防。此外，在洛伐他汀引起的肝毒性发作后给予甲羟戊酸，尽管继续药物治疗，但仍能有效逆转毒性。这些发现表明，高剂量洛伐他汀对家兔的毒性是阻断甲羟戊酸合成的高度夸大的药理作用的结果。然而，洛伐他汀治疗的家兔口服甲羟戊酸代谢的主要产物胆固醇，反而增加了肝脏和肾脏的损伤，这表明洛伐他汀的毒性源于对细胞活力至关重要的甲羟戊酸非固醇代谢物的消耗。
Lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, has been shown to be highly effective in lowering serum cholesterol in animals and humans and thus represents a promising approach to the treatment and prevention of cardiovascular disease. During the preclinical safety assessment of lovastatin, oral doses that were tolerated by dogs, rats and mice were found to be lethal to rabbits in subacute studies. Postmortem findings in rabbits consisted of centrilobular hepatic necrosis, frequently accompanied by renal tubular necrosis and occasionally gallbladder necrosis. The liver lesions were associated with up to 300-fold elevations in serum aspartate and alanine aminotransferase activities, whereas the kidney lesions resulted in accumulations of serum urea nitrogen and creatinine. The organ damage was preceded by a progressive decline in food consumption and loss of body weight. All histopathological and serum biochemical changes induced by lovastatin were completely prevented by coadministration of mevalonate, the product of the inhibited HMG-CoA reductase enzyme. In addition, administration of mevalonate after the onset of lovastatin-induced hepatotoxicity effectively reversed the toxicity despite continued drug treatment. These findings indicated that the toxicity of high doses of lovastatin to rabbits is a consequence of a highly exaggerated pharmacologic action in blocking mevalonate synthesis. However, supplementation of lovastatin-treated rabbits with oral doses of the major product of mevalonate metabolism, cholesterol, paradoxically enhanced the liver and kidney damage, which suggested that the toxicity of lovastatin stemmed from depletion of a nonsterol metabolite(s) of mevalonate critical for cell viability.