Cholesterol biosynthesis inhibition

Rate-limiting enzyme in cholesterol biosynthesis inhibition by statins results in reduction of plasma LDL-cholesterol levels. 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Among the many compounds that have been examined for their hypocholesterolemic or cholesterol biosynthesis inhibition properties are di-phenylacetylindanedione , ethyl 2-methyl-2-phenoxypropionate, l-(2-aminoethyl)-4-(p-chlorodiphenylmethyl)piperazine 2, or,a-diphenyl-P-(4-pyridyl)ethanol 20,25-diazacholesterol 3 4-amino-IH-pyrazolo[3,4-d] pyrimldlne, l-methyl-4-piperldyl bis(4-chlorophenoxy)acetate, 4-phen-oxyphenol methanesulfonate , 2-methyl-2-[ -(1,2,3,4-tetrahydro-1-naph-thyl)phenoxyIpropionic acid, I-benziloyl-4-benzylpiperazine hydrochlorr... 

The statins lower cholesterol by inhibiting the en zyme 3 hydroxy 3 methylglutaryl coenzyme A reduc tase which is required for the biosynthesis of meva Ionic acid (see Section 26 10) Mevalonic acid is an obligatory precursor to cholesterol so less mevalonic acid translates into less cholesterol... 

Scheme 1. Sites of inhibition of cholesterol biosynthesis by Mevacor and zaragozic acid A.

A class of cholesterol lowering drugs that inhibit 3-hydroxy-3-methylglutary 1-CoA reductase, the rate-limiting enzyme step in cholesterol biosynthesis. 

A series of hypocholesteremic agents were isolated from Monascus and named monacolin J, K, and L. These polyketides were first isolated from cultures of Penicillium citrinum and they can inhibit specifically the enzyme controlling the rate of cholesterol biosynthesis. They are currently used in China in traditional and modem medicine. 

Ajoene has antitumor activity, inhibits cholesterol biosynthesis, modulates membrane-dependent functions of immune cells, inhibits protein prenylation83 and is an anti-leukaemia agent for acute myeloid leukaemia.85 In antithrombotic assays, the Z isomer is more active than the E isomer.84... 

Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, interrupting the conversion of HMG-CoA to mevalonate, the rate-limiting step in de novo cholesterol biosynthesis. Reduced synthesis of LDL and enhanced catabohsm of LDL mediated through LDL-Rs appear to be the principal mechanisms for lipid-lowering effects. 

Cho SY, Kim JH, Paik YK (1998) Cholesterol biosynthesis from lanosterol differential inhibition of sterol delta 8-isomerase and other lanosterol-converting enzymes by tamoxifen. Mol Cells 8(2) 233-239... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Recently nicotinic acid has been found to lower serum cholesterol in hypercholesteremia, and also in normal persons and rabbits (A3, F2). It was shown that the hypercholesteremia, induced by a 48-hour fast, could be completely corrected by giving the animals large doses of nicotinic acid during the fast. In contrast to nicotinic acid, nicotinamide does not lower the cholesterol level (M10). Several explanations are offered for the action of nicotinic acid (1) it inhibits cholesterol biosynthesis, (2) it interferes with coenzyme A, and (3) it involves a hitherto unknown pharmacologic effect. The renewed clinical interest in nicotinic acid induced us to look for a more specific and sensitive assay for nicotinic acid (B7, M8). 

The therapeutic class that uniquely exemplifies lactone prodrugs are the statins, i.e., the cholesterol-lowering agents that act by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.34). This microsomal enzyme catalyzes conversion of HMG-CoA to mevalonate, an important rate-limiting step in cholesterol biosynthesis. Cholesterol synthesis occurs mainly... 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Statins are compounds that inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, and they are the world s best-selling drugs and are used for lowering cholesterol. Statins are well studied and are believed to be quite safe. Because they reduce the levels of cholesterol, the precursor of the bile acids, statins may be the ideal drugs to use for BA-loweiing in these GI tract diseases. 

Mouse lanosterol 14a-Me demethylase (P 450DM) A steroidal oxime that inhibits cholesterol biosynthesis 126... 

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

Rosuvastatin (Crestor ) is the most recent HMG-CoA reductase inhibitor to be widely approved for the treatment of hypercholesterolemic patients. It has established an impressive record of clinical efficacy and is often prescribed to patients that do not respond well to earlier HMG-CoA reductase inhibitors (Schuster, 2003). This fully synthetic statin, developed by Astra-Zeneca and Shionogi Research Laboratories, has been shown to potently inhibit cholesterol biosynthesis in rat hepatocytyes (IC50 =1.12 nM). By comparison, pravastatin (5) was > 100-fold less active in the same assay (IC50 =198 nM) (Hirai et al., 1993 Watanabe et al., 1997). 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Menendez, R., R. Mas, A. M. Amor, I. Rodeiros, R. M. Gonzalez, and J. L. Alfonso. Inhibition of cholesterol biosynthesis in cultured fibroblasts by D-003, a mixture of very long chain saturated fatty acids. Pharmacol Res... 

Menendez, R., S. I. Fernandez, A. Del Rio, et al. Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts. Biol Res... 

Inhibition of cholesterol biosynthesis (% of control) (human hepatocyte cells) io- M 10- M... 

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