China
Africa
Explore chapters and articles related to this topic
Molecular Mechanisms for Statin Pleiotropy and Possible Clinical Relevance in Cardiovascular Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Brian Yu, Nikola Sladojevic, James K. Liao
The primary mechanism of action for all statins is competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol. HMG-CoA reductase catalyzes a four-electron deacetylation, converting HMG-CoA to L-mevalonate and coenzyme A (Fig. 10.1). Lovastatin, simvastatin, and pravastatin are fungal-derived inhibitors of HMG-CoA reductase (type 1 statins), while fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are synthetically derived (type 2 statins) (Endo, 2010). There are three main structures within each compound (Fig. 10.2): (1) the HMG-like moiety mimicking HMG-CoA (in the form of a lactone ring); (2) a hydrophobic ring structure that plays a role in binding of statin to HMG-CoA reductase; (3) side groups on the rings that alter solubility and pharmacokinetic properties (Istvan, 2003). For instance, atorvastatin, simvastatin, lovastatin, and fluvastatin are relatively lipophilic, while rosuvastatin and pravastatin are relatively hydrophilic due to the polar methyl sulfasomidine group and hydroxyl group, respectively. Lipophilic statins can cross cell membranes by cell diffusion, while rosuvastatin and pravastatin require organic anion-transporting polypeptide 1B1 transporters, and are therefore more selective for hepatic tissues (Schachter, 2005). However, hydrophilic statins also exert extrahepatic effects in animals and human studies. It is likely there are yet unknown mechanisms for hydrophilic statins to enter non-hepatic cells, explaining their action on cell types such as endothelial cells.
Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
Statins are drugs used to lower the levels of cholesterol reducing the risk of cardiovascular diseases (Watanabe and Serizawa, 1998). They are inhibitors of the 3β-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-controlling enzyme of the biosynthesis of cholesterol. A number of statins is present in the market, including pravastatin, which was introduced in 1989 with the name of “Mevalotin” in Japan by Sanyo Pharma Inc. and later commercialized also in the United States by Bristol-Myers Squibb, USA. Pravastatin derives from the naturally occurring compound compactin but it was shown to have better pharmacokinetics properties (Yoshino et al., 1986; Serizawa, 1996). Compactin was first identified in the 1970s by Sanyo Pharma Inc. in the fungus Penicillium citrinum, which is used to produce this molecule through fermentation (Arai et al., 1988). Pravastatin derives from the stereoselective hydroxylation of compactin at the C6 position (Hosobuchi et al., 1993) that is achieved thanks to the action of a bacterial cytochrome P450 (Fig. 17.3). Biotransformation of compactin into pravastatin.
Medicinal Mushrooms
Published in Anil K. Sharma, Raj K. Keservani, Surya Prakash Gautam, Herbal Product Development, 2020
Temitope A. Oyedepo, Adetoun E. Morakinyo
Over the years, researchers have discovered that certain mushrooms, especially Pleurotus, have the ability to lower cholesterol (Bobek et al., 2001). Further work has discovered statins, the secondary metabolites, as the most likely compound responsible for this action (Alam et al., 2011). Lovastatin (mevinolin) is a statin that occurs in most of the basidiomycetes just like many other fungi. It is a powerful inhibitor of HMG-CoA reductase, the main rate-limiting enzyme in cholesterol production. Lovastatin analysis could serve as another marker for species with elevated levels of this compound. This should, however, be merged with the fact that quite high amounts of mushroom powder would be necessary to effect any action (Lo et al., 2012).
High yield production of lipid and carotenoids in a newly isolated Rhodotorula mucilaginosa by adapting process optimization approach
Published in Biofuels, 2023
Ravi Gedela, Ashish Prabhu, Venkata Dasu Veeranki, Pakshirajan Kannan
In oleaginous yeast, the hydrophilic substrate is consumed via the de novo pathway, and the lipid accumulation proceeds with the depletion of nitrogen compound, which in turns activate AMP deaminase. This activity leads toa series of cascade reactions, which disturbs the TCA cycle in mitochondria and splits the ATP-citrate lyase and acetyl-CoA and oxaloacetate. Further, the acetyl CoA is carboxylated in to malonyl CoA which is the first step of lipid synthesis, and then followed a by series of enzymatic reactions catalyzed by a complex of fatty acid synthases, which ultimately leads to the synthesis of triacyl glycerol. Further in yeast such as Rhodoturula sp that is capable of synthesizing carotenoids, which initiates by the conversion of acetyl CoA to 3 hydroxyl-3 methylglutaryl-CoA catalyzed by 3 hydroxyl-3 methylglutaryl-CoA synthase. Consequently, the HMG- CoA is reduced to mevalonic acid by HMG-CoA reductase and the cascade of reaction takes place for the production of isopentenyl diphosphate (IPP), which is further subjected to an isomerization reaction to form dimethylallyl pyrophosphate (DMAPP), and the addition of 3 molecules of IPP to DMAPP results in geranylgeranyl pyrophosphate (GGPP). The GGPP undergoes a condensation reaction catalyzed by phytoene synthase to form phytoene and finally converted to β-carotene [18]. The biochemical pathway for the formation of lipids and carotenoids in Rhodotorula sp is depicted in Figure S1 (Supplementary Material).
Reproductive outcomes in rat female offspring from male rats co-exposed to rosuvastatin and ascorbic acid during pre-puberty
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Gabriel Adan Araujo Leite, Thamiris Moreira Figueiredo, Tainá Louise Pacheco, Marina Trevizan Guerra, Janete Aparecida Anselmo-Franci, Wilma De Grava Kempinas
Among the lipid-lowering drugs, statins are considered effective due to their efficient reduction of total cholesterol in the blood (Endres 2006; Istvan 2003; Tandon et al. 2005). Statins decrease cholesterol concentrations by inhibiting the enzyme 3-hydroxy-3-methylglutharyl coenzyme A reductase (HMG-CoA reductase) (Istvan and Deisenhofer 2001; Jiménez and Ferre 2011) and preventing the conversion of HMG-CoA to mevalonate, thus reducing intermediate isoprenoids and cholesterol formation (Adam and Laufs 2008; Istvan 2003). The incidence rate of statin prescription to treat hypercholesterolemia in the pediatric population represents 63% of all pharmacotherapies (Liberman, Berger, and Lewis 2009); however, there are no apparent available data specifically for rosuvastatin prescription.
Atorvastatin ameliorated PM2.5-induced atherosclerosis in rats
Published in Archives of Environmental & Occupational Health, 2023
Hongmei Yao, Xingxing Zhao, Lili Wang, Yi Ren
In the present study, atorvastatin (ATO), one of the most widely-used statins, was employed to investigate if amelioration of PM2.5-induced atherosclerosis development could be achieved. Statins, the inhibition of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, can effectively decrease the LDL level and meanwhile increase the HDL level.18–20 It is common sense that statins have a lipid-lowering effect. Recently, statins were found to have anti-atherogenic effects, because the lipid-lowering effect of statins could slow the formation of atherosclerotic plaque, suppress smooth muscle cell proliferation and aggregation, reduce the size of atherosclerotic plaques, and prevent from further development of atherosclerotic plaque.21–23 As previously reported, atorvastatin inhibited HMG-CoA reductase and blocked the reaction of HMG-CoA to methylpentanoic acid, which significantly reduces cholesterol synthesis and neutralizes cholesterol concentrations in plasma and tissues.24 Because of the decrease of cholesterol level in the liver, the inhibition of LDL receptor genes was lifted, and thus LDL receptor density in the liver increased, which resulted in high concentrations of LDL molecules in the plasma being taken up and cleared by the liver. As represented in Table 1, in our PM2.5 - atorvastatin treated model, TC, TG, and LDL levels decreased significantly, demonstrating that atorvastatin presented an obvious lipid-lowing effect. Increasing LDL levels could provoke the formation of atherosclerosis by vasoconstriction, inflammation, proliferation of smooth muscle cells, and degradation of collagen fibers.16