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Inhibition of prenyltransferase activity by statins in both liver and muscle cell lines is not causative of cytotoxicity.

Gee, RH, Spinks, JN, Malia, JM, Johnston, JD, Plant, NJ and Plant, KE (2015) Inhibition of prenyltransferase activity by statins in both liver and muscle cell lines is not causative of cytotoxicity. Toxicology, 329. pp. 40-48.

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Abstract

As inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, statins are an important first-line treatment for hypercholesterolemia. However, a recognized side-effect of statin therapy is myopathy, which in severe cases can present as potentially fatal rhabdomyolysis. This represents an important impediment to successful statin therapy, and despite decades of research the molecular mechanisms underlying this side-effect remain unclear. Current evidence supports a role for reduced levels of mevalonate pathway intermediates, with the most accepted hypothesis being a reduction in isoprenoids formation, leading to faulty post-translational modifications of membrane-associated proteins. We have undertaken a comprehensive analysis of the impact of nine statins on two human cell lines; Huh7 hepatoma and RD rhabdomyosarcoma. In both cell lines, concentration-dependent inhibition of prenylation is observed for cerivastatin and simvastatin, which could be rescued with the pathway intermediate mevalonate; in general, muscle cells were more sensitive to this effect, as measured by the levels of unprenylated Rap1A, a marker for prenylation by geranylgeranyl transferase I. Concentration-dependent toxicity was observed in both cell lines, with muscle cells again being more sensitive. Importantly, there was no correlation between inhibition of prenylation and cell toxicity, suggesting they are not causally linked. The lack of a causal relationship was confirmed by the absence of cytotoxicity in all cell lines following exposure to specific inhibitors of geranylgeranyl transferases I and II, and farnesyl transferase. As such, we provide strong evidence against the commonly accepted hypothesis linking inhibition of prenylation and statin-mediated toxicity, with the two processes likely to be simultaneous but independent.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Biochemical Sciences
Authors :
AuthorsEmailORCID
Gee, RHUNSPECIFIEDUNSPECIFIED
Spinks, JNUNSPECIFIEDUNSPECIFIED
Malia, JMUNSPECIFIEDUNSPECIFIED
Johnston, JDUNSPECIFIEDUNSPECIFIED
Plant, NJUNSPECIFIEDUNSPECIFIED
Plant, KEUNSPECIFIEDUNSPECIFIED
Date : 2 March 2015
Identification Number : 10.1016/j.tox.2015.01.005
Uncontrolled Keywords : Cholesterol, HMG COA, Prenylation, Statin toxicity
Related URLs :
Additional Information : NOTICE: this is the author’s version of a work that was accepted for publication in Toxicology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Toxicology, 329, March 2015, DOI 10.1016/j.tox.2015.01.005.
Depositing User : Symplectic Elements
Date Deposited : 27 Jan 2015 10:35
Last Modified : 27 Jan 2015 14:33
URI: http://epubs.surrey.ac.uk/id/eprint/807118

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