title: Daunorubicin metabolism in leukemic cells isolated from patients with acute myeloid leukemia.
abstract: BACKGROUND
  Anthracyclines like daunorubicin (DNR) are important drugs in the treatment of acute myeloid leukaemia (AML). In vitro studies have shown that cellular metabolism of anthracyclines could play a role in drug resistance. Currently, it is not known what enzyme is responsible for anthracycline metabolism in leukemic cells.
  
  
  OBJECTIVE
  To study C-13 reduction of DNR to daunorubicinol (DOL) in leukemic cells isolated from patients with AML and to determine the most important enzyme involved.
  
  
  METHODS
  Mononuclear blood cells from 25 AML patients were isolated at diagnosis and used in a metabolic assay to determine the % DOL formed. mRNA and western blot analysis were performed on the 2 most likely candidates for anthracycline metabolism; carbonyl reductase 1 (CR1) and aldoketoreductase 1A1 (AKR1A1). DNR and DOL concentrations were determined by HPLC.
  
  
  RESULTS
  We found a large interindividual variation (up to 47-fold) in leukemic cell DNR metabolism. The specific CR1 inhibitor zeraleone analogue 5 significantly inhibited DNR metabolism with a mean inhibitory effect of 68 %. No correlation between mRNA levels of the enzymes and metabolism were found. Cellular DNR metabolism correlated significantly with CR1 protein expression, determined by western blot, (p < 0.05, R2 = 0,229) while no significant correlation was found with AKR1A1 protein expression.
  
  
  CONCLUSIONS
  DNR metabolism in AML cells shows a pronounced interindividual variability. Our results support that CR1 is the most important enzyme for conversion of DNR to DOL in AML cells. This information could in the future be used to genotype CR1 and possibly help to individualise dosing.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Karolinska Institute/Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Alex
authors.initials: A
authors.lastname: Bogason
authors.forename: Michéle
authors.initials: M
authors.lastname: Masquelier
authors.forename: Pierre
authors.initials: P
authors.lastname: Lafolie
authors.forename: Cristine
authors.initials: C
authors.lastname: Skogastierna
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Sigurd
authors.initials: S
authors.lastname: Vitols
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D001711:Biotransformation; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C000847:daunorubicinol; D003630:Daunorubicin