Preferential oxidation of cardiac mitochondrial DNA following acute intoxication with doxorubicin.
The purpose of this investigation was to determine whether acute doxorubicin intoxication causes a preferential accumulation of 8-hydroxydeoxyguanosine (8OHdG) adducts to mitochondrial DNA (mtDNA) as opposed to nuclear DNA (nDNA), particularly in cardiac tissue. Adult male rats received a single i.p. bolus of doxorubicin (15 mg/kg) and were killed 1-14 days later. Acute intoxication with doxorubicin caused a 2-fold greater increase in 8OHdG adducts to mtDNA compared to nDNA, the concentration of adducts to both nDNA and mtDNA being 20%-40% greater for heart as opposed to liver. For both tissues, the relative abundance of adducts was highest at the earliest time-point examined (24 h) and decreased to control values by 2 weeks. The temporal dilution of 8OHdG adducts was not the result of cell hyperplasia and was only partially due to amplification of the mitochondrial genome, most probably via an increase in DNA copy number rather than a stimulation of mitochondrial biogenesis.
Palmeira
C M
CM
Department of Biochemistry and Molecular Biology, University of Minnesota, School of Medicine, Duluth 55812, USA.
Serrano
J
J
Kuehl
D W
DW
Wallace
K B
KB
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D018736:DNA Adducts; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D018736:DNA Adducts; D004272:DNA, Mitochondrial; D004317:Doxorubicin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine