Inhibition, HMG-CoA reductase

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

The answer is a. (Hardman, pp 885-887.) Lovastatin decreases cholesterol synthesis in the liver by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the synthetic pathway This results in an increase in LDL receptors in the liver, thus reducing blood levels for cholesterol. The intake of dietary cholesterol must not be increased, as this would allow the liver to use more exogenous cholesterol and def eat the action of lovastatin. 

Because HMG CoA reductase occurs before a branch point in the biosynthetic pathway, complete inhibition of the enzyme by cholesterol would necessarily deprive the cell of many other intermediates, some of which are important in cell growth and division. A group of drugs known as statins are widely used to reduce plasma cholesterol concentration by inhibiting HMG CoA reductase. Interest is now rising in the possible use of statins as anticancer drugs due to their impact on reducing the production of mediators of cell proliferation. 

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. 

Endo A. (1985) Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. J Med Chem 28 401 05. 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

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). 

HMG-CoA Reductase Inhibitors Statins inhibit HMG-CoA reductase, the enzyme synthesizing mevalonic acid (a key step in cholesterol biosynthesis). These drugs are indicated to treat hypercholesterolemia and to reduce LDL cholesterol. 

Mechanism of Action An antihyperlipidemic that inhibits HMG-CoA reductase, the enzyme that catalyzes the early step in cholesterol synthesis. Therapeutic Effect Decreases LDL cholesterol, VLDL, and plasma triglyceride levels. Slightly increases HDL cholesterol concentration. 

Also known as statins. HMG CoA reductase (Hydroxymethyl-Glutaryl Coenzyme A Reductase) inhibitors block the synthesis of cholesterol in liver by competitively inhibiting HMG CoA reductase activity, also cause depletion of critical intracellular pools of sterols and increased transcription of LDL receptors leading to enhanced removal from plasma of LDL cholesterol and LDL precursors. They also reduce hepatic synthesis of VLDL, increase plasma HDL. Reduction of LDL occurs over 4-6 weeks. 

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

Mechanism of Action Inhibit HMG-CoA reductase, preventing the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis Depletion of cellular cholesterol stimulates the production of cell surface receptors that recognize LDL, leading to increased catabolism of LDL cholesterol ... 

HGURE 21-45 Inhibitors of HMG-CoA reductase. A comparison of the structures of mevalonate and four pharmaceutical compounds that inhibit HMG-CoA reductase. 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

Statins inhibit HMG-CoA reductase and reduce cellular cholesterol synthesis (1). Lower intracellular cholesterol concentrations cause over-expression of the LDL receptor in the plasma membrane of hepatocytes. This overexpression increases the clearance of circulating LDL, reducing plasma concentrations of LDL cholesterol. 

After screening 8000 microorganisms, three novel inhibitors of HMG-CoA reductases were found at Sankyo (Tokyo, Japan), Mevastatin among them. The open form inhibits HMG-CoA reductase with a K value of 1 nM and influences dramatically the biosynthesis of cholesterol, just like the later developed analogs Lovastatin and Simvastatin (Figure 13.15, below). 

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

In vitro, allicin and related compounds inhibit HMG-CoA reductase, which is involved in cholesterol biosynthesis (see Chapter 35 Agents Used in Hyperlipidemia). Several clinical trials have investigated the lipid-lowering potential of garlic. Some have shown significant reductions in cholesterol and others no effect. The most recent meta-analysis suggested a minor (5%) reduction of total cholesterol that was insignificant when dietary controls were in place. 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

Statin Drugs and CHD. Statin drugs are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that act by inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. The statins are now the most commonly prescribed drugs for the treatment of hypercholesterolemia. They can reduce plasma total cholesterol by 20-42%, LDL-cholesterol by 25-55% and triglycerides by 10-35%. In addition,... 

A feedback mechanism operates in which intracellular free cholesterol inhibits HMG-CoA reductase. When the diet is rich in cholesterol, intracellular cholesterol increases in the liver and the biosynthesis of cholesterol is suppressed. Conversely, a low-cholesterol diet, but one with adequate triglyceride, stimulates cholesterol biosynthesis. 

The reductase kinase (RK), which phosphorylates (and inhibits) HMG-CoA reductase, is itself controlled through phosphorylation (activated) by reductase kinase kinase (RKK). There... 

The LDL particle (10% triglyceride content) is finally taken up into the liver and other tissues by the LDL receptor. The LDL receptor is a six-domain transmembrane protein whose synthesis is under negative feedback regulation, such that when intracellular cholesterol levels are raised, new LDL receptors are not formed, thereby preventing the uptake of further cholesterol from plasma LDL. LDL also inhibits HMG-CoA reductase and hence cholesterol synthesis by negative feedback inhibition. Absence of the LDL receptor leads to hypercholesterol-aemia and atherosclerosis, as there is a decrease in the rate at which LDLs are removed from the plasma. 

H-10) HMG CoA reductase. This is an important rate-limiting step in cholesterol synthesis. Drugs that act at this step to inhibit HMG CoA reductase can lower blood chole.sterol. Normally, excess cholesterol inhibits HMG CoA reductase by negative feedback on its activity and synthesis, providing a natural control mechanism for cholesterol synthesis. Hereditary differences result in differences in feedback effects. In certain people there is a marked increase in serum cholesterol on increasing cholesterol intake, whereas in others, there is little increase, as the feedback mechanism is functioning more actively. 

One example for our current work is the structure analysis of human HMG-CoA reductase. This enzyme catalyzes an important step in our body s own production of cholesterol. Millions of people in the U.S.A. alone, who have high levels of cholesterol in their blood, take drugs that inhibit HMG-CoA reductase to lower the cholesterol level and thus reduce the risk of artherosclerosis. These inhibitors are known as statins. We now know the tree-dimensional structure of the catalytic portion of human HMG-CoA reductase we also know how substrates and inhibitors bind to the enzyme. This adds to our knowledge and will enable us to think about even better inhibitors. 

Drugs known as statins inhibit HMG-CoA reductase and thereby prevent... 

An interesting species difference might be pointed out. The above HMG-CoA reductase inhibitors inhibit HMG-CoA reductase from a variety of animals, and reduce serum cholesterol in humans, rabbits and dogs, but do not reduce serum chr lesterol in rats and mice (Sakono et ai, 1996). 

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