Comparative anthracycline metabolism in rats: loss of marcellomycin fluorescence.
The in vitro metabolism of marcellomycin by rat tissue fractions showed conversion of marcellomycin to 7-deoxypyrromycinone, bisanhydropyrromycinone, and an as yet unidentified compound by rat liver homogenate, microsomes, cytosol, and mitochondria, and purified hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase, under anaerobic conditions and in the presence of reduced nicotinamide adenine dinucleotide phosphate. All these fractions except the purified reductase subsequently induced a progressive loss of fluorescence. Mitochondria, however, were much less active than microsomes, cytosol, and homogenate in inducing this latter phenomenon. Marcellomycin was converted to 7-deoxyaglycones only partially by nuclei. No loss of fluorescence was observed with this subcellular fraction. No loss of fluorescence was observed when doxorubicin or daunorubicin were incubated under similar conditions. The appearance of a compound with distinct spectrophotometric properties was demonstrated by absorbance spectrometry. The formation of a compound with different fluorescent characteristics was excluded, as was the binding of the aglycones to subcellular components. The activity inducing the loss of fluorescence was studied in greater detail with cytosol. It predominated in the liver and required both an electron donor and anaerobic conditions. The optimal pH for the reaction was between 7.5 and 8.0. Our results suggest the existence of an enzymatic pathway capable of converting the fluorescent nucleus of marcellomycin to a nonfluorescent metabolite.
Dodion
P
P
Tamburini
J M
JM
Fox
B M
BM
Riggs
C E
CE
Bachur
N R
NR
D000818:Animals; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D005453:Fluorescence; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis; D009279:Naphthacenes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013379:Substrate Specificity
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D009279:Naphthacenes; C015338:marcellomycin; D009251:NADPH-Ferrihemoprotein Reductase