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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) act as competitive HMG-CoA reductase inhibitors; HMG-CoA reductase is the first enzyme in the mevalonate pathway for synthesizing cholesterol in the liver that begins with the conversion of acetyl-CoA to mevalonate. They lower LDL-C by 18% to 55%, but are not as effective in treating familial hypercholesterolemia, an autosomal dominant disorder; this holds in particular for people with homozygous defects usually in either the LDL receptor or apolipoprotein B genes, which both are responsible for LDL clearance from the blood. Statins have been found to reduce cardiovascular disease; side/adverse effects of statins are muscle pain, increased risk of diabetes mellitus (statins and niacin are associated with increased risk of impaired glucose control and development of new-onset diabetes; Zafrir and Jain, 2014), abnormalities in liver enzyme, liver damage, cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction (Golomb et al., 2008; Thompson et al., 2016) myopathies and muscles inflammation (Abd and Jacobson, 2011). For a “Protocol for analyses of adverse event data from randomized controlled trials of statin therapy” see Reith et al. (2016). In contrast to earlier findings, e.g., those published by Gao et al. (2012), who reported that regular use of statins was associated with a modest reduction in PD risk, a new study performed by Liu et al. (2017) came to the conclusion that the use of statins in particular lipophilic ones, is associated with a significantly higher risk of developing symptoms of Parkinson’s disease.
Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Susana Barros, Ana M. Coimbra, Nélson Alves, Marlene Pinheiro, José Benito Quintana, Miguel M. Santos, Teresa Neuparth
A broad description of the experimental conditions of the chronic toxicity test was presented in the first part of this study, which aimed at evaluating the effects of SIM at ecological relevant endpoints (morphometry, reproduction and embryonic development), biochemical (hepatic cholesterol and triglyceride levels) and molecular markers (transcription of genes related to cholesterol branch of the mevalonate pathway in the liver) (Barros et al. 2018). Briefly, the experiment consisted of 5 treatments with two replicates each: control (0.0002% acetone), and 4 increasing nominal concentrations of SIM (8, 40, 200, and 1000 ng/L, prepared in 0.0002% acetone). SIM (CAS no. 79902-63-9; ≥97% HPLC) was obtained from Sigma Aldrich®. The concentrations of SIM used in the present study were based upon our previous research (Neuparth et al. 2014), which observed a severe impact on the reproduction of the amphipod Gammarus locusta, after an exposure to SIM at environmentally relevant concentrations (ng/L range).