Abstract
Atorvastatin (a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor) is a widely used cholesterol-lowering drug, which is recognized for its potential hepatotoxicity. This study investigated in vitro effects of this agent on hepatic tissue respiration, ATP content, caspase activity, urea synthesis and histology. Liver fragments from Taylor Outbred and C57Bl/6 mice were incubated at 37°C in Krebs-Henseleit buffer continuously gassed with 95% O2: 5% CO2 in the presence and absence of atorvastatin. Phosphorescence O2 analyzer that measured dissolved [O2] as a function of time was used to monitor cellular mitochondrial O2 consumption. The caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin was used to monitor caspase activity. The rates of hepatocyte respiration (μM O2 min-1 mg-1) in untreated samples were 0.15 ± 0.07 (n = 31). The corresponding rates for samples treated with 50 nM (therapeutic concentration), 150 nM or 1.0 μM atorvastatin for ≤13 h were 0.13 ± 0.05 (n = 19), p = 0.521. The contents of hepatocyte ATP (pmol-1 mg-1) in untreated samples were 40.3 ± 14.0 and in samples treated with 1.0 μM atorvastatin for ≤4.5 h were 48.7 ± 23.9 (p = 0.7754). The concentrations of urea (mg/dL mg-1, produced over 50 min) for untreated samples were 0.061 ± 0.020 (n = 6) and for samples treated with 1.0 μM atorvastatin for ≤6 h were 0.072 ± 0.022 (n = 6), p = 0.3866. Steadily, hepatocyte caspase activity and histology were unaffected by treatments with up to 1.0 μM atorvastatin for ≤6 h. Thus, the studied murine model showed preserved hepatocyte function and structure in the presence of high concentrations of atorvastatin.
Highlights
Statins, 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, are the most effective class of drugs that treat hypercholesterolemia
Bioenergetics of liver tissue treated with atorvastatin To assess the effects of atorvastatin on liver tissue bioenergetics, specimens from ten Taylor Outbred (TO) mice and three C57Bl/6 mice were incubated at 37°C with 50 nM, 150 nM or 1.0 μM atorvastatin and analyzed for cellular O2 consumption and ATP content as a function of time
This study investigated whether atorvastatin impairs hepatocyte cellular bioenergetics
Summary
3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors, are the most effective class of drugs that treat hypercholesterolemia. These agents reduce hepatocyte cholesterol, which results in up-regulation of the low-density lipoprotein (LDL) receptors and increased clearance of LDL-cholesterol from the plasma. Elevations of liver alanine and aspartate aminotransferases (ALT and AST) are well-recognized adverse events of atorvastatin [2,3,4], occurring in about 0.5% of patients, usually in the first few months of therapy [5,6]. Since other lipid-lowering compounds increase liver aminotransferases, it has been debated whether statin-. Impaired bioenergetics or respiration entails interferences with any of these processes
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