Superoxide anion production by doxorubicin analogs in heart sarcosomes and by mitochondrial NADH dehydrogenase.
This study investigates the effects of daunorubicin, 4-demethoxy-daunorubicin, 11-deoxydaunorubicin, 5-imino-daunorubicin, doxorubicin, 4'-epidoxorubicin and the new derivative 4'-iodo-4'-deoxydoxorubicin, on superoxide anion production in heart sarcosomes and by mitochondrial NADH dehydrogenase. In cardiac sarcosomes all the anthracyclines tested enhanced NADPH-dependent superoxide formation which followed Michaelis-Menten kinetics and their Vmax were similar to that of doxorubicin except 5-iminodaunorubicin which did not affect superoxide production and 4'-iodo-4'-deoxydoxorubicin which showed significantly lower Vmax and Km. The superoxide formation by NADH dehydrogenase in the presence of anthracyclines appeared to follow saturation kinetics, depending by NADH. 4-Demethoxydaunorubicin and 4'-epidoxorubicin showed Vmax higher than that of doxorubicin although the Km values were similar. By contrast 5-iminodaunorubicin failed to increase superoxide production over control levels and 4'-Iodo-4'-deoxydoxorubicin hardly enhanced superoxide production by NADH dehydrogenase. A marked difference of superoxide formation rate was shown for the molecules tested in our in vitro system. The behaviour displayed in vitro by the imino- and iodo-derivatives well correlate to their moderate cardiotoxicity in vivo. For the other molecules tested, the poor correlation between the in vitro production of superoxides and the in vivo cardiotoxicity degree might depend on the pharmacokinetic steps which may modify the cardiac effects of these anthracyclines.
Gervasi
P G
PG
Istituto di Mutagenesi e Differenziamento C N R, Università di Pisa, Italy.
Agrillo
M R
MR
Lippi
A
A
Bernardini
N
N
Danesi
R
R
Del Tacca
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D003579:Cytochrome Reductases / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D013481:Superoxides; D004317:Doxorubicin; D013482:Superoxide Dismutase; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase