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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.
Novel Microbial Compounds as a Boon in Health Management
Published in Jyoti Ranjan Rout, Rout George Kerry, Abinash Dutta, Biotechnological Advances for Microbiology, Molecular Biology, and Nanotechnology, 2022
Shubha Rani Sharma, Rajani Sharma, Debasish Kar
Atherosclerosis is a dreaded disease that is caused due to accumulation of atheromatous plaque within the arterial wall. A variety of antiatherosclerotic therapies have been introduced in the last two decades. The level of cholesterol is lowered by statins by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) (Nicholls et al., 2007). Currently, there are several statins prescribed as antihypocholesterolemic drugs. Certain statins like compactin and mevastatin were isolated from Penicillium brevicompactum and Penicillium citrinum and used as promising antibiotics. Also, the derivates of compactin witnessed overwhelming medical success. Lovastatin was isolated from the broths of the Monascus rubber and Aspergillus terreus as a secondary metabolite (Alberts et al., 1980). Lovastatin was the first commercially available statin, approved by the FDA in 1987. Simvastatin, a major cholesterol-lowering drug that is a semisynthetic derivative of lovastatin is also a microbial product. Another promising molecule, pravastatin (US$ 3.6 billion per year), was synthesized from compactin by Streptomyces acidophilus (Serizawa and Matsuoka, 1991) and Actinomadura sp. (Peng and Demain, 1998) through several biotransformation processes. A synthetic drug, obtained from natural statins, atorvastatin, inhibits HMG-CoA reductase, has been the principal antihypocholesterolemic drug of the entire pharmaceutical industry for many years in terms of market share. Additionally, there were several genera that were very commonly involved in the production of statins are Hypomyces, Paecilomyces Doratomyces, Gymnoascus, Pleurotus, Eupenicillium, Phoma, and Trichoderma (Alarcón et al., 2003).
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.
Pomegranate juice supports therapeutic –treatment of atorvastatin against maternal hypercholesterolemia induced retinopathy of rat offspring
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Hassan IH EL-Sayyad, Hebattallah A Abd El-Gallil, Heba A El-Ghawet
Statins are also a class of medication involved in reducing blood cholesterol levels by inhibiting the cholesterol synthesizing enzyme, 3 hydroxyl 3 methylglutaryl coenzyme A [19], decreased mevalonate formation involved in synthesis of cholesterol [20], increased endothelial function and improved the activity of antioxidant [21]. Simvastatin also attenuated the cholesterol induced damage in the rabbit hippocampus [22], alleviated cell death of hippocampal cells and improved the synaptic function in AD mice model [23]. Statins can also contribute to improve dry eye disease, corneal ulcer, glaucoma, uveitis, cataracts, proliferative retinopathy, diabetic retinopathy, macular degeneration, and choroidal melanoma [24].
Integration of biological and statistical models toward personalized radiation therapy of cancer
Published in IISE Transactions, 2019
Xiaonan Liu, Mirek Fatyga, Teresa Wu, Jing Li
We apply the integrated model to the dataset according to the steps in Figure 3. Recall that the integrated model includes a step for consistency correction, for the case where the population fraction of complication, , is smaller than the sample fraction of complication, . In our dataset, while in the published literature on population-based studies (Tucker et al., 2012). Therefore, consistency correction is needed. Furthermore, to choose the optimal tuning parameters, we adopt a model selection criterion called AICc, which includes a correction for the original AIC under small sample sizes (Hurvich and Tsai, 1989). The results from the integrated model are as follows: Among all the patient-specific variables included in the dataset, six are selected using AICc: diabetes status, prostate volume, PSA, statins use, ADT status, T-stage. The optimal is found to be 0.154. These results are consistent with findings in the literature. For example, statins are a class of drugs often prescribed by doctors to help lower cholesterol levels in the blood. Statins use is negatively related to the probability of complication, indicating that the use of statins might be protective against the development of the 2+ acute rectal complication by patients. At least one biological mechanism behind this seemingly protective effect has been suggested (Malek, 2015), and a relatively recent study reported a similar result, namely a negative association between acute rectal complication during pelvic RT and the use of statins (Wedlake et al., 2012). This corroborates our finding. PSA is a blood test that is commonly used to detect prostate cancer; the higher the level of PSA, the higher the chance the patient has prostate cancer. Finally, knowing that the range of is between zero and one, the optimal found by the integrated model is small. This is consistent with prior findings (Bentzen et al., 2010) and agrees with clinical expectation; the rectum is a serial organ, and it is well-known that serial organs tend to have small (Gulliford et al., 2012; Li et al., 2012).