Mechanism of the antimycin A-mediated enhancement of t-butylhydroperoxide-induced single-strand breakage in DNA.
Inhibitors of complex III increased the DNA strand scission induced by t-butylhydroperoxide (tB-OOH) and cumene hydroperoxide but did not affect DNA damage induced by H2O2. The hypothesis that these effects are selectively linked to inhibition of the electron transport from cytochrome b to cytochrome c1 is validated by the following observations: (1) two complex III inhibitors, antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, enhanced the tB-OOH-induced DNA cleavage over the same concentration range as that in which inhibition of oxygen consumption was observed; (2) the complex III inhibitor-mediated enhancement of tB-OOH-induced DNA damage was abolished by the complex I inhibitor rotenone or by glucose omission, and (3) the enhancing effects of antimycin A were not observed in respiration-deficient cells. The mechanism whereby the complex III inhibitors potentiate DNA cleavage promoted by tB-OOH was subsequently investigated with intact as well as permeabilized cells. H2O2, produced at the level of mitochondria via a Ca2+-dependent process, was found to account for the enhancing effects of antimycin A.
Guidarelli
A
A
Istituto di Farmacologia e Farmacognosia and Centro di Farmacologia Oncologica Sperimentale, Università di Urbino, Via S. Chiara, 27, 61029 Urbino (PS), Italy.
Clementi
E
E
Brambilla
L
L
Cantoni
O
O
D000968:Antimycin A / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000494:pharmacology; D007951:Leukemia, Myeloid; D008928:Mitochondria / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology*; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D020122:tert-Butylhydroperoxide
D001555:Benzene Derivatives; D004277:DNA, Single-Stranded; D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D010545:Peroxides; D012402:Rotenone; C001333:2-(n-heptyl)-4-hydroxyquinoline N-oxide; D000968:Antimycin A; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D014450:Electron Transport Complex III; D005947:Glucose; C007164:cumene hydroperoxide; D002118:Calcium