Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.
FEMS Yeast Res. 2010 Mar;10(2):188-98. doi: 10.1111/j.1567-1364.2009.00593.x. Epub 2009 Nov 3.
Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.
他汀类药物，用于治疗高胆固醇血症，是发达国家最常开的药物之一。然而，相当一部分使用者出现肌肉毒性症状，目前，肌肉毒性的分子机制仍不清楚。在这项研究中，酿酒酵母被用作模型系统，以进一步了解阿托伐他汀毒性的分子机制。阿托伐他汀处理的酵母细胞显示出明显的形态畸形，细胞活力降低，并且对线粒体功能紊乱非常敏感。阿托伐他汀处理细胞的补充实验表明，细胞活力丧失和线粒体功能障碍都是由于固醇合成途径的扰动引起的。通过用固醇合成途径的各种代谢物补充他汀类药物处理的细胞进一步研究了这一点，这些代谢物被认为是细胞功能所必需的。麦角固醇、辅酶 Q 和血红素前体都不能有效地预防他汀类药物诱导的线粒体破坏和细胞死亡。然而，添加香叶基香叶基焦磷酸和法尼基焦磷酸显著恢复了细胞活力，尽管这些并不能克服 petite 诱导。这突出了他汀类药物毒性的多效性，但已经确定蛋白质异戊烯基化的破坏是他汀类药物诱导酵母细胞死亡的主要机制之一。
