title: Geranylgeraniol prevents the cytotoxic effects of mevastatin in THP-1 cells, without decreasing the beneficial effects on cholesterol synthesis.
abstract: OBJECTIVE
  Statins, inhibitors of hydroxymethylglutaryl-CoA reductase, reduce the intracellular synthesis of cholesterol and prevent the onset of atherosclerosis. They also decrease the synthesis of isoprenoid molecules, such as the side chain of ubiquinone and geranylgeranyl pyrophosphate. As a consequence, statins impair mitochondrial metabolism and the activation of small monomeric GTPases (such as Rho and Ras), causing toxic effects. To date, a successful strategy to prevent statin toxicity is lacking.
  
  
  METHODS
  In human monocytic THP-1 cells, we measured the synthesis of cholesterol and isoprenoids, mitochondrial electron flow, the activity of RhoA and Rac, cell death and proliferation.
  
  
  RESULTS
  Mevastatin reduced the synthesis of cholesterol, geranylgeranyl pyrophosphate and ubiquinone, mitochondrial electron transport, activity of RhoA and Rac, and cell proliferation, accompanied by increased cell death. Geranylgeraniol, a cell-permeable analogue of geranylgeranyl pyrophosphate, reversed all these effects of mevastatin, without affecting its ability to reduce cholesterol synthesis. Notably, geranylgeraniol was more effective than the addition of exogenous ubiquinone, which rescued mitochondrial respiratory activity and reversed mevastatin cytotoxicity, but did not alter the decrease in cell proliferation. The same results were obtained in human liver HepG2 cells.
  
  
  CONCLUSIONS
  Geranylgeraniol had a broader protective effect against the cytotoxicity of statins than exogenous ubiquinone. Therefore, geranylgeraniol may be a more useful and practical means of limiting the toxicities of statins, without reducing their efficacy as cholesterol lowering agents.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, Via Santena, Torino, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Campia
authors.forename: C
authors.initials: C
authors.lastname: Lussiana
authors.forename: G
authors.initials: G
authors.lastname: Pescarmona
authors.forename: D
authors.initials: D
authors.lastname: Ghigo
authors.forename: A
authors.initials: A
authors.lastname: Bosia
authors.forename: C
authors.initials: C
authors.lastname: Riganti
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis*; D004224:Diterpenes / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology
chemical_list: D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D014451:Ubiquinone; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin; C017338:geranylgeraniol