In search of a substance that lowers plasma cholesterol levels, Endo et al. tested more than 6000 fungi species, which finally, in 1973, led to the discovery of ML-236B . ML-236B was subsequently termed mevastatin; however, due to its severe side-effects, it never reached the market. Nevertheless, mevastatin is still frequently used in in vitro studies. Lovastatin (mevinolin) was the first statin to be approved by the Food and Drug Administration (FDA) in 1987. Currently, lovastatin, simvastatin, pravastatin, fluvastatin and atorvastatin are available (Fig. 3). The new substance, rosuvastatin, was approved by the FDA in August 2003. Pitavastatin, as a very recent addition to the group, is currently available in Japan only. Statins are well tolerated and generally considered safe. Cerivastatin, however, was withdrawn from the market in August 2001, because it had the highest incidence of the overall rare side-effect rhabdomyolysis, and it is assumed to be involved in a total of 52 deaths worldwide . Early data suggested that cholesterol reduction with statins may cause an increase in the incidence of cancer . Furthermore, experimental data suggested that statins could increase the occurrence of several types of cancer in rodents . However, data from a meta-analysis  and a recent analysis from the Scandinavian Simvastatin Survival Study (4S) have helped large ly to dispel this concern. In fact, in the 4S data there was no difference in mortality from and incidence of cancer between the simvastatin and the placebo group 10 years after study termination .
Statins are currently subdivided according to different characteristics, such as their chemical structure (open ring vs closed ring structure), their origin (synthetic vs natural, the latter being derived from fungal fermentation), and their solubility (hydrophilic vs lipophilic, Fig. 3). Lipophilic statins would be expected to penetrate cell membranes more effectively, thus eliciting more pleiotropic effects . However, the evidence suggests otherwise, because hydrophilic statins and lipophilic ones appear to share the same pleiotrop-ic activity. Furthermore, only statins with an open ring structure inhibit HMG-CoA reductase and lead to a decrease in plasma cholesterol. Statins with a closed-ring structure must undergo metabolisation to an open ring structure before activity is initiated, although these substances may still confer pleiotropic effects before metabolisa-tion occurs.
Fig. 3. Chemical structure and classification of statins. Statins are subgrouped according to their origin (natural vs synthetic), their chemical structure (open vs closed ring) and their solubility (lipophilic vs hydrophilic). See text for details
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