ubiquinone and geranylgeraniol

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.. 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.. 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.. 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.

Topics: Cell Death; Cell Line, Tumor; Cell Proliferation; Cholesterol; Diterpenes; Electron Transport; Hep G2 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mitochondria; Monocytes; Terpenes; Ubiquinone

Evidence has been obtained indicating that free farnesol (F-OH) can be utilized for isoprenoid biosynthesis in mammalian cells. When rat C6 glial cells and an African green monkey kidney cell line (CV-1) were incubated with [3H]F-OH, radioactivity was incorporated into cholesterol, ubiquinone (CoQ) and isoprenylated proteins. The incorporation of label from [3H]F-OH into cholesterol in C6 and CV-1 cells was blocked by squalestatin 1 (SQ) which specifically inhibits the conversion of farnesyl pyrophosphate (F-P-P) to squalene. This result strongly suggests that cholesterol, and probably CoQ and protein, is metabolically labeled via F-P-P. SDS-PAGE analysis of the delipidated protein fractions from C6 and CV-1 cells revealed several labeled polypeptides. Consistent with these proteins being modified by isoprenylation of cysteine residues. Pronase E digestion released a major labeled product with the chromatographic mobility of [3H]farnesyl-cysteine (F-Cys). A different set of polypeptides was labeled when C6 and CV-1 cells were incubated with [3H]geranylgeraniol (GG-OH). Both sets of proteins appear to be metabolically labeled by [3H]mevalonolactone, and [3H]-labeled F-Cys and geranylgeranyl-cysteine (GG-Cys) were liberated from these proteins by Pronase E treatment. These cellular and biochemical studies indicate that F-OH can be used for isoprenoid biosynthesis and protein isoprenylation in mammalian cells after being converted to F-P-P by phosphorylation reactions that remain to be elucidated.

Topics: Animals; Cell Line; Chlorocebus aethiops; Cholesterol; Cysteine; Diterpenes; Electrophoresis, Polyacrylamide Gel; Farnesol; Glioma; Kinetics; Mevalonic Acid; Neoplasm Proteins; Protein Biosynthesis; Protein Prenylation; Proteins; Rats; Tritium; Tumor Cells, Cultured; Ubiquinone

The ability of adult B. pahangi and D. immitis to utilize [14C]-mevalonate for the biosynthesis of isoprenoid compounds was investigated. Both filariae appeared to be unable to synthesize squalene and sterols de novo. They did, however, synthesize ubiquinone 9, a family of dolichol isoprenologs, and predominantly, the short-chain isoprenoid alcohol, geranyl geraniol. In addition, B. pahangi and D. immitis apparently were unable to synthesize a menaquinone (Vitamin K2) from [14C]-menadione.

Topics: Animals; Brugia; Cholesterol; Dirofilaria immitis; Diterpenes; Dolichols; Female; Filarioidea; Male; Mevalonic Acid; Palmitates; Terpenes; Ubiquinone; Vitamin K