GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFICIENCY SEVERELY RESTRICTS THE BIOTRANSFORMATION OF DAUNORUBICIN IN HUMAN ERYTHROCYTES

Recognition and analysis of distinct mechanisms by which primaquine an d other hemolytic drugs activate the hexose monophosphate shunt (HMS) have suggested a hitherto unsuspected pharmacogenetic interaction betw een daunorubicin metabolism and glucose-6-phosphate dehydrogenase (G6P D) deficiency. Because this deficiency is very common, and because ant hracyclines are indispensable antitumor antibiotics that are biotransf ormed mainly by carbonyl reductase, we have compared the reductase-med iated conversion of daunorubicin to daunorubicinol and the conversion of doxorubicin to doxorubicinol in G6PD-deficient and nondeficient ery throcytes. We found that even without G6PD deficiency, the HMS dehydro genases selectively limited daunorubicin metabolism, as contrasted wit h that of doxorubicin. The milder GdA(-) variety of G6PD deficiency re stricted the biotransformation of daunorubicin at therapeutic levels, in hemolysates and intact erythrocytes, within 15 minutes, for at leas t 24 hours. The bioconversion defect was even more severe in Gd Medite rranean G6PD deficiency. Primaquine aldehyde competed with daunorubici n as a substrate for carbonyl reductase. These studies show that HMS d ehydrogenase activity controls carbonyl reductase-dependent biotransfo rmation. New issues arise concerning possible effects of G6PD deficien cy on the oncolytic and toxic properties of anthracyclines that are ef fective substrates for carbonyl reductase and also on non-xenobiotic r eactions catalyzed by this enzyme.