Acute ethanol administration oxidatively damages and depletes mitochondrial dna in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants.
Ethanol metabolism causes oxidative stress and lipid peroxidation not only in liver but also in extra-hepatic tissues. Ethanol administration has been shown to cause oxidative degradation and depletion of hepatic mitochondrial DNA (mtDNA) in rodents, but its in vivo effects on the mtDNA of extra-hepatic tissues have not been assessed. We studied the effects of an acute intragastric ethanol administration (5 g/kg) on brain, heart, skeletal muscle, and liver mtDNA in mice. Ethanol administration caused mtDNA depletion and replacement of its supercoiled form by linearized forms in all tissues examined. Maximal mtDNA depletion was about similar (ca. 50%) in all organs studied. It occurred 2 h after ethanol administration in heart, skeletal muscle, and liver but after 10 h in brain. This mtDNA depletion was followed by increased mtDNA synthesis. A secondary, transient increase in mtDNA levels occurred 24 h after ethanol administration in all organs. In hepatic or extra-hepatic tissues, mtDNA degradation and depletion were prevented by 4-methylpyrazole, an inhibitor of ethanol metabolism, and attenuated by vitamin E, melatonin, or coenzyme Q, three antioxidants. In conclusion, our study shows for the first time that ethanol metabolism also causes oxidative degradation of the mitochondrial genome in brain, heart, and skeletal muscles. These effects could contribute to the development of (cardio)myopathy and brain injury in some alcoholic patients. Antioxidants prevent these effects in mice and could be useful in persevering drinkers.
Mansouri
A
A
Institut National de la Santé et de la Recherche Médicale Unité 481 and Centre de Recherches de l'Association Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France.
Demeilliers
C
C
Amsellem
S
S
Pessayre
D
D
Fromenty
B
B
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015139:Blotting, Southern; D001921:Brain / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D000431:Ethanol / Q000633:toxicity*; D000077604:Fomepizole; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects*; D008929:Mitochondria, Heart / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects; D016877:Oxidants / Q000633:toxicity; D011720:Pyrazoles / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014451:Ubiquinone / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D002492:Central Nervous System Depressants; D004272:DNA, Mitochondrial; D016877:Oxidants; D011720:Pyrazoles; D014451:Ubiquinone; D014810:Vitamin E; D000431:Ethanol; D000077604:Fomepizole; D008550:Melatonin; D013936:Thymidine