Statin-induced muscle toxicity

The clinical severity of statin-induced muscle toxicity is clearly influenced by variability in enzymes modulating statin disposition (absorption, distribution, metabolism, and elimination, ADME) (Fig. 1) [40], While many statins undergo phase I oxidation (atorvastatin, fluvastatin, lovastatin, simvastatin), the impact of phase I oxidation on others (pitavastatin, pravastatin, rosuvastatin) is very limited [41],... 

Mareedu RK, Modhia FM, Kanin El, Linneman JG, Kitchner T, McCarty CA, Krauss RM, Wilke RA (2009) Use of an electronic medical record to characterize cases of intermediate statin-induced muscle toxicity. Prev Cardiol 12 88-94... 

Table 2 Genetic predisposing factors for statin-induced muscle toxicity...

Chemical Biology Approach to Suppression of Statin-Induced Muscle Toxicity... 

Figure 10.3 Geranylgeranyl pyrophosphate (GGPP) suppresses statin-induced muscle toxicity. C2C12 myotubes were treated for 48 h with simvastatin in the absence or...

Figure 10.4 Rab prenylation events are involved in statin-induced muscle toxicity, (a) Co-treatment with statin and GGPP restores ATP levels. However, addition of BMS3, an inhibitor of...

We thus reasoned that if we suppressed the effects of statins on muscle toxicity by co-treatment with GGPP, we could then determine whether Rac/Rho prenylation or Rab prenylation was the important factor by additional treatment with GGTase inhibitors. This experiment revealed that treatment with simvastatin, GGPP, and GGTI-2133 did not decrease ATP levels, but treatment with simvastatin, GGPP, and BMS3 did result in a decrease in cellular ATP levels (Figure 10.4). These results showed that a Rab prenylation event was responsible for statin-induced muscle toxicity. 

Figure 10.5 High-throughput screening identified G66976 (a) as a suppressor of statin-induced muscle toxicity, (b) Chemical structure of BMS3. (c) The suppressive effects of G66976 are, as in the case of GGPP, lost by further addition of BMS3.

This study provides evidence that Rab prenylation is important to statin-induced muscle toxicity, and that it is possible to identify suppressive small molecules that should not inhibit the beneficial effects of statins on blood cholesterol levels. The use of small molecules to dissect biosynthetic pathways is certainly not new, but affords a precise and rapid understanding of the phenotypic consequences of cellular perturbations. For the future, modern chemical biology techniques, including affinity labeling of isoprenoids [11], provide an attractive opportunity to identify the specific Rabs responsible for statin-induced muscle toxicity. As a common laboratory tool compound, G66976 is unlikely to become a clinical candidate. 

Further screening has the power to identify chemical series with improved prop-erties and more selective inhibition of statin-induced muscle toxicity. 

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