Compactin toxicity

Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway (Fig. 1). In contrast to desmosterol and other late-stage lipid-soluble intermediates, HMG is water-soluble, and there are alternative metabolic pathways for its breakdown when HMG-CoA reductase is inhibited so that there is no buildup of potentially toxic precursors. Therefore, of the more than 30 enzymes involved in the biosynthesis of cholesterol, HMG-CoA reductase was a natural target. Substances that have a powerful inhibitory effect on this enzyme, including ML236B (compactin), were first discovered by Endo in a fermentation broth of Penicillium citrinum in the... 

Millions of people in the world suffer from cardiovascular disease, and it is a leading cause of death in both men and women. Elevation in plasma low-density lipoprotein (LDL) cholesterol levels is a major risk factor for myocardial infarction (heart attack) in these patients. Drugs to reduce dyslipidemia have included niacin and the fibrate class, but each of these has clinical limitations, such as low efficacy or toxic side effects. The development of HMG-CoA reductase inhibitors, or statins, has had an enormous clinical impact on the treatment of heart disease and prevention of heart attack, and these are taken by tens of millions of patients worldwide [1]. One of the first such drugs, lovastatin, was discovered in the 1970s as a fungal natural product [2] and lowered lipid levels in animals and healthy volunteers. Problems with the development of another early statin, compactin, halted advancement of lovastatin to regular clinical use until the late 1980s. Since then. 

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