Massive conversion of guanosine to 8-hydroxy-guanosine in mouse liver mitochondrial DNA by administration of azidothymidine.
As typical mitochondrial myopathy has been reported to be expressed among many patients with AIDS treated with long-term azidothymidine (AZT) therapy, we examined changes in mouse liver mitochondrial DNA (mtDNA) after 4-week administration of AZT. Even below 1/10th the dose given to the patients (AZT, 1 mg/kg/day), 25% of the total deoxyguanosine (dG) was converted to be 8-hydroxy-deoxyguanosine (8-OH-dG). 38% of the total dG was converted to 8-OH-dG with AZT 5 mg/kg/day. In vitro, the conversion of dG to 8-OH-dG was demonstrated by incubating mtDNA in the oxygen radical producing system containing NADH and KCN treated mitochondrial inner membrane. Thus it is concluded that, by lack of repairing system, damaged mtDNA with AZT results in impaired mitochondrial respiratory chain causing oxygen radicals which are responsible for 8-OH-dG formation. These results suggest that the oxygen damage of mtDNA is the primary cause of mitochondrial myopathy with AZT therapy.
Hayakawa
M
M
Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
Ogawa
T
T
Sugiyama
S
S
Tanaka
M
M
Ozawa
T
T
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D006151:Guanosine / Q000031:analogs & derivatives*; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013481:Superoxides / Q000032:analysis; D015215:Zidovudine / Q000494:pharmacology*
D004272:DNA, Mitochondrial; D013481:Superoxides; D006151:Guanosine; C046215:8-hydroxyguanosine; D015215:Zidovudine