HypothesisSelenoprotein synthesis and side-effects of statins
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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