Potential role of nonstatin cholesterol lowering agents

Although statins, 3β‐hydroxy‐3β‐methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsi...

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Bibliographic Details
Published in:IUBMB life 2011-11, Vol.63 (11), p.964-971
Main Authors: Trapani, Laura, Segatto, Marco, Ascenzi, Paolo, Pallottini, Valentina
Format: Article
Language:English
Subjects:
3‐hydroxy 3‐methylglutaryl coenzyme A reductase
Animals
Anticholesteremic Agents - pharmacology
Anticholesteremic Agents - therapeutic use
cholesterol
Cholesterol - biosynthesis
Cholesterol - blood
Clinical Trials as Topic
Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors
Farnesyl-Diphosphate Farnesyltransferase - metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use
hypercholesterolemia
Hypercholesterolemia - drug therapy
Hypercholesterolemia - enzymology
inhibition
Intramolecular Transferases - antagonists & inhibitors
Intramolecular Transferases - metabolism
Molecular Targeted Therapy
oxidosqualene cyclase
squalene epoxidase
Squalene Monooxygenase - antagonists & inhibitors
Squalene Monooxygenase - metabolism
squalene synthase
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Summary:Although statins, 3β‐hydroxy‐3β‐methylglutaryl coenzyme A reductase (HMGR) inhibitors, have revolutionized the management of cardiovascular diseases by lowering serum low density lipoproteins, many patients suffer from their side effects. Whether the statin side effects are related to their intrinsic toxicity or to the decrease of HMGR main isoprenoid end products, which are essential compounds for cell viability, is still debated. In addition to HMGR, the key and rate limiting step of cholesterol synthesis, many enzymes are involved in this multi‐step pathway whose inhibition could be taken into account for a “nonstatin approach” in the management of hypercholesterolemia. In particular, due to their unique position downstream from HMGR, the inhibition of squalene synthase, farnesyl diphosphate farnesyltransferase (FDFT1), squalene epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase (OSC) should decrease plasma levels of cholesterol without affecting ubiquinone, dolichol, and isoprenoid metabolism. Thus, although FDFT1, SQLE and OSC are little studied, they should be considered as perspective targets for the development of novel drugs against hypercholesterolemia. Here, structure–function relationships of FDFT1, SQLE, and OSC are reviewed highlighting the advantages that the downstream inhibition of HMGR could provide when compared to the statin‐based therapy. © 2011 IUBMB IUBMB Life, 63(11): 964–971, 2011
ISSN:1521-6543
1521-6551
DOI:10.1002/iub.522