Elsevier

The Lancet

Volume 363, Issue 9412, 13 March 2004, Pages 892-894
The Lancet

Hypothesis
Selenoprotein synthesis and side-effects of statins

https://doi.org/10.1016/S0140-6736(04)15739-5Get rights and content

Summary

Statins are possibly the most effective drugs for the prevention and treatment of hypercholesterolaemia and coronary heart disease. They are generally well tolerated, however, they do cause some unusual side-effects with potentially severe consequences, most prominently myopathy or rhabdomyolysis and polyneuropathy. We noted that the pattern of side-effects associated with statins resembles the pathology of selenium deficiency, and postulated that the mechanism lay in a well established, but often overlooked, biochemical pathway—the isopentenylation of selenocysteine-tRNA[Ser]Sec. A negative effect of statins on selenoprotein synthesis does seem to explain many of the enigmatic effects and side-effects of statins, in particular, statin-induced myopathy.

Section snippets

Hypothesis

We postulate that statins interfere with the enzymatic isopentenylation of selenocysteine-tRNA[Ser]Sec(Sec-tRNA) and prevent its maturation to a functional tRNA molecule, resulting in a fall in available seleno-proteins. Our reasoning behind this hypothesis is detailed below.

Biochemistry

Sec-tRNA governs the expression of all selenoproteins,13 but is only functional after certain post-transcriptional modifications, one of which is the isopentenylation of adenosine 37. Selenoprotein synthesis is greatly decreased in cell culture and in transgenic mice in which the isopentenylation site in Sec-tRNA has been genetically ablated.14, 15

Isopentenylation of Sec-tRNA is undertaken by tRNA isopentenyl transferase, which uses isopentenyl pyrophosphate (IPP) as a substrate.16 IPP, in

Clinical and pathological features

Individuals with statin-induced myopathy have similar clinical and pathological features to those with syndromes associated with severe selenoprotein deficiency.

Myopathic syndromes caused by selenium deficiency are not uncommon. For example, Keshan disease, an endemic cardiomyopathy in rural areas of China, is associated with insufficient selenium intake and enteroviral infection.19, 20 Second, long-term parenteral nutrition can lead to severe selenium deficiency frequently associated with

Testing of hypothesis

The most stringent way to test our hypothesis would be to assess whether statin users show a decreased amount of mature functional Sec-tRNA in relevant tissues or cell types. A surrogate approach, enabling such assessment, would be the measurement of selenoprotein activity, which could be approximated by the measurement of selenoprotein immunoreactivity. In general, a decrease in selenoprotein activity should be noted. Not all seleno-proteins, however, would be equally affected, and there might

Conclusion

Our hypothesis provides a testable explanation for several of the apparently unrelated effects and side-effects of statins, and could lead to an improved understanding of the mechanisms of action of these drugs. However, we do not propose selenium substitution as a general cotreatment to statins, since we believe that the beneficial effects of statins in cardiovascular disease are, to a considerable extent, due to selenoprotein inactivation or secondary compensatory mechanisms triggered by

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