title: The anti-carcinogenic effect of statins in a rat model correlates with levels and synthesis of ubiquinone.
abstract: Ubiquinone (Q) is a product in the cholesterol synthesis pathway and is an essential component of the respiratory chain in the mitochondrial membrane. In addition, extra-mitochondrial Q has anti-oxidative properties and this fraction is increased during carcinogenesis. The aim of the present study was to investigate if extra-mitochondrial level of Q is affected by statin treatment in a rat model for liver cancer, and if this change correlates with inhibited carcinogenesis. To do this we isolated sub-cellular fractions of rat livers from a previous experiment where we have shown anti-carcinogenic effects of statins. The levels of Q(8), Q(9) and Q(10) were analysed with liquid chromatography-mass spectrometry. The Q(9)-levels, constituting the major part of Q in rats, were not significantly affected in any of the sub-cellular compartments. The levels of Q(10), constituting a minor part of Q in rats but the major part of Q in humans, were significantly decreased by about 60% in the statin treated rats. The decrease was present in all sub-cellular compartments, but was most pronounced in the cytosol. There was a significant correlation between extra-mitochondrial Q(10) levels and inhibited carcinogenesis. No such correlation was observed with extra-mitochondrial Q(9). The reduced Q(10)-levels might be explained by the reduced availability of isoprene units during statin treatment, shifting the synthesis towards isoforms with shorter side-chains. In line with this hypothesis there were increased levels of Q(8)-levels during statin treatment. The results support our previous suggestion that at least part of the anti-carcinogenic effect of statins in our rat model is mediated by effects on synthesis of Q. We also demonstrate a shift in the Q-synthesis pathway towards isoforms with shorter side-chains during statin treatment. The ratio between the different Q-isoforms might be used as a more sensitive marker of statin-induced inhibition of Q than measuring total Q levels.
authors: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden.
authors: Jure
authors: J
authors: Acimovic
authors: Anita
authors: A
authors: Lövgren-Sandblom
authors: Lennart C
authors: LC
authors: Eriksson
authors: Linda
authors: L
authors: Björkhem-Bergman
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000201:enzymology*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D014451:Ubiquinone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D016588:Anticarcinogenic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D014451:Ubiquinone