6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 25–28 October 2004 - Washington, DC, USA

DO STATINS ENHANCE HIV THERAPY-INDUCED MITOCHONDRIAL TOXICITY?

Antiviral Therapy 2004; 9(6):L25 (abstract no. 37)

MP de Baar¹, KGM Smolders¹, M Buitelaar¹, JT Dekker¹ and AH Klerkx^2
1Primagen, Amsterdam, The Netherlands; and ²Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands

Antiretroviral therapy causes mitochondrial toxicity-related adverse events, as well as dyslipidaemia with lower HDL-cholesterol and higher LDL and total cholesterol levels as a result. This dyslipidaemia is often treated with statins to reduce the total and LDL-cholesterol levels. Several studies have shown that statins also affect the mitochondria both morphologically and physiologically, occasionally resulting in mitochondrial dysfunction. We investigated the effects of statin treatment on mtDNA levels in PBMC, using the Retina Mitox assay that quantifies the mitochondrial and nuclear DNA ratio in one tube. A group of seven individuals with elevated cholesterol levels were treated for 2 months with 40 mg simvastatin daily, whereas a control group of six individuals with elevated triglyceride levels were treated with 100 mg ciprofibrate daily. Samples were taken at day 0 and after 2 months and analysed for mtDNA content in a blinded way. There were no significant changes in mtDNA over time in the control group on ciprofibrate (P=0.292), whereas the group on simvastatin showed a significant increase from 361 to 429 mean copies mtDNA per cell (P=0.032). Statins inhibit HMG-CoA reductase, thereby reducing the synthesis of cholesterol, as well as intermediates in the cholesterol biosynthesis pathway like farnesyl pyrophosphate, which also acts as precursor for coenzyme Q10 (Co-Q10). Co-Q10 plays an important role in the electron transport of the oxidative phosphorylation in mitochondria and depletion might lead to disorders in the energy metabolism. Our first hypothesis is that depletion of Co-Q10 results in increased levels of mtDNA to facilitate an increase of mRNA encoding for proteins, such as the COX family of proteins, involved in the oxidative phosphorylation. Furthermore, cells were cultured in the presence of nucleoside RT inhibitors (ddC, ddI, d4T), simvastatin, ciprofibrate and combinations thereof. We observed higher toxicity on cells that were exposed to nucleoside analogues in combination with statins relative to any of the other cultures. Since treatment with nucleoside RT inhibitors can result in mitochondrial toxicity-related adverse events, our second hypothesis is that this mitochondrial toxicity might be worsened by the treatment with statins due to a combined toxic effect on the mitochondria.

2004-10-25
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