Flint O P, Masters B A, Gregg R E, Durham S K
Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York 13057, USA.
Toxicol Appl Pharmacol. 1997 Jul;145(1):91-8. doi: 10.1006/taap.1997.8131.
The cholesterol-lowering HMG CoA reductase inhibitors (HMGRI), pravastatin and lovastatin, have been associated with skeletal myopathy in humans and in rats. In a previous in vitro study, HMGRI-induced changes in neonatal rat skeletal muscle cells were characterized by reversible inhibition of protein synthesis and loss of differentiated myotubes at concentrations markedly lower than those inducing enzyme leakage. Myotoxicity was determined to be directly related to inhibition of HMG CoA reductase, since mevalonate, the immediate product of HMG CoA reductase metabolism, abrogated the drug-induced changes. Farnesol, geranylgeraniol, and squalene are metabolites of mevalonate. Squalene, formed from farnesol by squalene synthase, is the first metabolite solely committed to cholesterol synthesis. In contrast, geranylgeraniol, formed by the addition of an isoprene group to farnesol, is the first metabolite uncommitted to cholesterol synthesis. The objective of the present study was to determine the role of inhibition of cholesterol synthesis in HMGRI-induced in vitro myotoxicity. HMGRI-treated neonatal rat skeletal muscle cultures were supplemented with farnesol and geranylgeraniol, and in another study, muscle cultures were exposed to two squalene synthase inhibitors (SSI), BMS-187745 and its prodrug ester, BMS-188494. Endpoints evaluated for both studies included protein synthesis ([3H]leucine incorporation), total cellular protein (a measure of cell loss), intra- and extracellular lactate dehydrogenase activity (a measure of membrane integrity), cholesterol biosynthesis ([14C]acetate incorporation), and morphology. HMG CoA reductase inhibitor-induced morphologic changes and inhibition of protein synthesis were significantly ameliorated by supplementation with farnesol and geranylgeraniol. In contrast to HMGRI-induced in vitro myotoxicity, SSI induced an irreversible, minimal cytotoxicity at close to maximum soluble concentrations. These results indicate that depletion of metabolites of geranylgeranyl pyrophosphate, and not inhibition of cholesterol synthesis, is the primary cause of HMG CoA reductase-induced myotoxicity.
降胆固醇的HMG CoA还原酶抑制剂（HMGRI），普伐他汀和洛伐他汀，已被证实与人类和大鼠的骨骼肌病有关。在之前的一项体外研究中，HMGRI诱导新生大鼠骨骼肌细胞发生的变化表现为蛋白质合成的可逆性抑制以及分化肌管的丧失，其浓度明显低于诱导酶泄漏的浓度。肌毒性被确定与HMG CoA还原酶的抑制直接相关，因为HMG CoA还原酶代谢的直接产物甲羟戊酸消除了药物诱导的变化。法尼醇、香叶基香叶醇和角鲨烯是甲羟戊酸的代谢产物。角鲨烯由法尼醇通过角鲨烯合酶形成，是唯一专门用于胆固醇合成的第一种代谢产物。相比之下，香叶基香叶醇是通过向法尼醇添加一个异戊二烯基团形成的，是第一种不专门用于胆固醇合成的代谢产物。本研究的目的是确定胆固醇合成抑制在HMGRI诱导的体外肌毒性中的作用。用HMGRI处理的新生大鼠骨骼肌培养物中添加了法尼醇和香叶基香叶醇，在另一项研究中，肌肉培养物暴露于两种角鲨烯合酶抑制剂（SSI），BMS - 187745及其前药酯BMS - 188494。两项研究评估的终点包括蛋白质合成（[³H]亮氨酸掺入）、总细胞蛋白（细胞损失的一种度量）、细胞内和细胞外乳酸脱氢酶活性（膜完整性的一种度量）、胆固醇生物合成（[¹⁴C]乙酸掺入）以及形态学。补充法尼醇和香叶基香叶醇可显著改善HMG CoA还原酶抑制剂诱导的形态学变化和蛋白质合成抑制。与HMGRI诱导的体外肌毒性相反，SSI在接近最大可溶浓度时诱导了一种不可逆的、最小的细胞毒性。这些结果表明，香叶基香叶基焦磷酸代谢产物的耗竭，而非胆固醇合成的抑制，是HMG CoA还原酶诱导肌毒性的主要原因。
