Glucose-6-phosphate dehydrogenase deficiency severely restricts the biotransformation of daunorubicin in human erythrocytes.
Recognition and analysis of distinct mechanisms by which primaquine and other hemolytic drugs activate the hexose monophosphate shunt (HMS) have suggested a hitherto unsuspected pharmacogenetic interaction between daunorubicin metabolism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Because this deficiency is very common, and because anthracyclines are indispensable antitumor antibiotics that are biotransformed mainly by carbonyl reductase, we have compared the reductase-mediated conversion of daunorubicin to daunorubicinol and the conversion of doxorubicin to doxorubicinol in G6PD-deficient and nondeficient erythrocytes. We found that even without G6PD deficiency, the HMS dehydrogenases selectively limited daunorubicin metabolism, as contrasted with that of doxorubicin. The milder GdA- variety of G6PD deficiency restricted the biotransformation of daunorubicin at therapeutic levels, in hemolysates and intact erythrocytes, within 15 minutes, for at least 24 hours. The bioconversion defect was even more severe in Gd Mediterranean G6PD deficiency. Primaquine aldehyde competed with daunorubicin as a substrate for carbonyl reductase. These studies show that HMS dehydrogenase activity controls carbonyl reductase-dependent biotransformation. New issues arise concerning possible effects of G6PD deficiency on the oncolytic and toxic properties of anthracyclines that are effective substrates for carbonyl reductase and also on non-xenobiotic reactions catalyzed by this enzyme.
Amitai
Y
Y
Department of Pharmacology, Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, IL 60612, USA.
Bhooma
T
T
Frischer
H
H
D000328:Adult; D000429:Alcohol Oxidoreductases / Q000097:blood*; D001667:Binding, Competitive; D001711:Biotransformation; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000097:blood*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000097:blood; D004912:Erythrocytes / Q000201:enzymology*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood*; D006801:Humans; D011319:Primaquine / Q000097:blood
D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C010013:adriamycinol; D011319:Primaquine; C000847:daunorubicinol; D003630:Daunorubicin