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L-Carnitine Prevents Mitochondrial and Metabolic Disturbances Induced by Very High Dose of Stavudine in Mice
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Background by authors: Stavudine (d4T) and other nucleoside reverse-transcriptase inhibitors (NRTIs) can induce side effects such as hepatic
steatosis, pancreatitis, and lactic acidosis. Some of these effects are thought to be due to an inhibition of mitochondrial DNA (mtDNA) replication, but other mechanism(s) may exist.
These researchers found L-Carnitine showed benefits regarding mitochondrial toxicities in mice which may or may not translate into benefit in humans. A human study is needed to show real benefit.
Researchers used a murine mouse model to assess the mitochondrial and metabolic effects of very high doses of d4T and to determine as to whether L-carnitine (a co-factor mandatory for the mitochondrial oxidation of long-chain fatty acids) is able to prevent these effects, if any.
D4T was given to mice for 2 weeks (wks) at the dose of 500 mg/kg/d (e.g., 37-fold the daily dose equivalent to the human dose per body area), whereas other mice received d4T (500 mg/kg/d) and L-carnitine (200 mg/kg/d). Mice were fasted for 48 hrs at the end of the treatments.
The study found that, at the dose of 500 mg/kg/d, d4T significantly decreased by 25 and 27% the in vivo oxidation of [U-14C] palmitic acid and plasma ketone bodies (KB), respectively, in comparison with control mice. Hepatic mitochondrial DNA (mtDNA) was ca.
Fifty percent (50%) of the control values, but the activities of complexes I and IV of the mitochondrial respiratory chain were not impaired and blood lactate
and pyruvate were unchanged.
Preliminary experiments showed that d4T increased hepatic triglycerides (TG) and decreased the expression of PPAR-a, a nuclear factor regulating fatty acid (FA) oxidation. In mice treated with d4T and L-carnitine, the in vivo oxidation of [U-14C] palmitic acid and plasma KB were no longer decreased. Moreover, L-carnitine afforded a partial protection against d4T-induced hepatic accumulation of TG and the expression of PPAR-a was partially restored.
The study researchers concluded based on these results in mice that altogether, these results suggest that, in our murine model, impairment of the respiratory chain may not be responsible for decreased FA oxidation and ketogenesis. Decreased hepatic expression of PPAR-a could be involved, but further investigations are needed to look for other mechanism(s). Importantly, L-carnitine is able to counteract the metabolic effects of very high doses of d4T, especially impairment of FA oxidation and increased hepatic TG.
Abst 724. Retrovirus Conference 2003, Feb 10-14. A IGOUDJIL. Hosp Beaujon, Clichy, France and INSERM Unite 393, Hosp Necker, Paris, France
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