Effects of high rosuvastatin doses on hepatocyte mitochondria of hypercholesterolemic mice

Abstract

Statins are the cornerstone of therapy for individuals with hyperlipidemia. The aim of this study was to analyze the undesirable effects of mild, moderate and high doses of rosuvastatin in CD-1 male mice who received a cholesterol-rich diet, focusing on the morphological and functional changes on hepatocyte mitochondria. In a mouse model we studied the combined administration of a cholesterol-rich diet along with mild and moderate doses of rosuvastatin (1, 2.5 or 5 mg/kg/day) during several days. After the animals were sacrificed, liver mitochondria were isolated for microscopic studies and to analyze the respiratory function. The respiratory control (state-3/state-4) was evaluated in mice who received high doses of rosuvastatin. Rosuvastatin doses higher than 20 mg/kg/day induced premature death in mice with a hypercholesterolemic diet, but not in mice with a cholesterol-free diet. Doses from 2.5 to 5 mg/kg/day also induced morphological and functional alterations in mitochondria but these hypercholesterolemic animals survived longer. Giving 1 mg/kg/day, which is close to the maximal therapeutic dose for humans, did not affect mitochondrial architecture or respiratory function after two months of treatment. We analyzed the effect of rosuvastatin on hepatic tissue because it is where statins are mainly accumulated and it is the main site of endogenous cholesterol synthesis. Our results contribute to understand the side effects of rosuvastatin in hypercholesterolemic mice, effects that could also affect humans who are intolerant to statins.

Statins Induce Locomotion and Muscular Phenotypes in Drosophila melanogaster That Are Reminiscent of Human Myopathy: Evidence for the Role of the Chloride Channel Inhibition in the Muscular Phenotypes

“…Interestingly, in contrast to the control group, the fluvastatintreated flies showed significantly larger mitochondria sizes (Figure 3E) and the number of round-like shaped mitochondria was remarkably higher (Figure 3F). In line with these results, several publications have pointed out that statins cause enlarged and round-like shaped mitochondria [89][90][91][92][93].…”

High doses of rosuvastatin induce impaired branched‐chain amino acid catabolism and lead to insulin resistance

“…Previous studies have suggested a link between rosuvastatin treatment and the development of new-onset diabetes (Ostrowska et al, 2015;Salunkhe et al, 2016;Yoon & Lee, 2013); however, the exact processes underlying this adverse effect of rosuvastatin remain unclear. We conducted detailed in vivo and in vitro investigations It should be noted that the doses of rosuvastatin used in the present studies (10 mg/kg in vivo and 25 μM in vitro), chosen based on the literature (Desjardins et al, 2008;Diaz-Zagoya et al, 2021;Mayanagi et al, 2008;Tijeras-Raballand et al, 2010;Zeybek et al, 2011), are much higher than those used in humans (0.1-1 mg/kg, Bjorkhem-Bergman et al, 2011), and that the in vitro concentrations are several orders of magnitude greater than the concentrations of the drug reported in human plasma (1-15 nM, Bjorkhem-Bergman et al, 2011). In this regard, the dose-response experiments showed that the lowest effective concentration of rosuvastatin in inhibiting Akt and GSK3β signaling in the mouse cell line C2C12 was 10 μM, which was ∼100-fold higher than the expected levels in plasma of patients on statins.…”

Onosma hispidum L. extract reverses hyperlipidemia, hypertension, and associated vascular dysfunction in rats

“…The next step was the preparation of liver homogenate by using a homogenizer. After the preparation of homogenate, the assay of HMG-CoA was carried out ( Rao and Ramakrishnan, 1975 , Díaz-Zagoya et al, 2021 ).…”