Potential for Statins in the Chemoprevention and Management of Hepatocellular Carcinoma

Amedeo Lonardo; Paola Loria


J Gastroenterol Hepatol. 2012;27(11):1654-1664. 

In This Article

What Are Statins?

Pure cholesterol, the molecular formula of which was established in 1888, was first extracted from gallstones and named cholesterine, namely "solid bile" in ancient Greek.[6] Medical science has progressed from an era when hypercholesterolemia was deemed to be a mere consequence of ageing—and thus atherosclerosis an unpreventable condition—to the present paradigm that atherosclerosis can be prevented through targeting hypercholesterolemia to reduce mortality.[6,7] This major shift in clinicians' attitude largely results from statins having been made available.

Cholesterol Synthesis Takes Place in Four stages:6

  1. condensation of three acetate units to form a 6-carbon intermediate, mevalonate;

  2. conversion of mevalonate to activated isoprene units;

  3. polymerization of six five-carbon isoprene units to form the 30-carbon linear squalene;

  4. cyclization of squalene to form the steroid nucleus, with a further series of changes to produce cholesterol.

The third reaction in the first stages is the committed and rate-limiting step: reduction of Hydroxy-Methyl-Glutaryl-Coenzyme A (HMGCoA) to mevalonate is the major point of regulation on the pathway to cholesterol (Fig. 1).

Figure 1.

Biosynthesis of cholesterol. The diagram shows the site of action of statins along the cholesterol biosynthetic pathway. Statins act on the key regulation step of cholesterol biosynthesis: the reduction of Hydroxy-Methyl-Glutaryl-Coenzyme A (HMGCoA) to mevalonate.8 Permission obtained to reproduce from Tobert JA Nat Rev Drug Discov 2003. Confirmation number 110191133 Order Date 08/09/2012.

The discovery of statins is due to a substantial extent to the pioneer work by the Japanese researcher Akira Endo influenced by his native rural environment, by the biography of the discoverer of penicillin Alexander Fleming, and by the high rate of heart attacks observed while working in the USA.[6]

In 1985, Brown and Goldstein were awarded the Nobel Prize in Physiology and Medicine for their discoveries on the regulation of cholesterol metabolism[9] and lovastatin received FDA approval to be commercialized in 1987.[6]

Statins (the chemical structure of which is depicted in Fig. 2) have now been tested in many large-scale clinical trials, involving 90 000 subjects who were followed for 5 years.[6] These studies have consistently shown that treatment with statins lowers plasma low-density lipoprotein (LDL) levels by 25–35% and reduces the frequency of heart attacks to the same extent. Statins are deemed to be the largest selling class of drugs currently taken by patients throughout the world.[6]

Figure 2.

Chemical structure of statins. The remarkable similarities existing among the ancestor molecules, compactin and lovastatin and those statins which are commercially available for clinical use.6 The figure is reused from the Proceedings of the Japan Academy, Ser. B (6), with permission.