title: Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia.
abstract: OBJECTIVE
  The present study aimed to investigate the role of expression of daunorubicin-metabolizing enzymes carbonyl reductase 1 and 3 (CBR1 and CBR3) on the in vitro cytotoxicity of daunorubicin in primary acute myeloid leukemia (AML) cells and the effect of genetic variants in CBR1 and CBR3 on the plasma pharmacokinetics of daunorubicin and daunorubicinol (DOL) in AML patients.
  
  
  METHODS
  RNA expression of CBR1 and CBR3, intracellular daunorubicin and DOL levels, and in vitro cytotoxicity of daunorubicin were measured in bone marrow mononuclear cells of 104 adult AML patients. Plasma pharmacokinetics of daunorubicin and DOL was measured in 24 patients receiving daunorubicin-based induction chemotherapy for AML.
  
  
  RESULTS
  Increased expression of CBR1 significantly reduced the in vitro cytotoxicity of daunorubicin and also positively correlated with intracellular DOL levels. Polymorphisms in CBR1 and CBR3 did not show any association with intracellular daunorubicin or DOL levels, but there was a trend towards significant increase in plasma daunorubicin systemic exposure in patients with a variant genotype for CBR1 polymorphism rs25678.
  
  
  CONCLUSIONS
  This pilot study suggests that CBR1 RNA expression may be helpful in identifying AML patients at risk of developing resistance or toxicity to daunorubicin due to increased formation of DOL. Further confirmation of these findings in a larger sample pool would be required to determine the applicability of these results. Inhibition of CBR1 can be an option to improve the efficacy and prevent toxicity related to the treatment. Influence of daunorubicin and DOL plasma levels on clinical outcome, if any, remains to be evaluated.
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, 632004, India.
authors.forename: Savitha
authors.initials: S
authors.lastname: Varatharajan
authors.forename: Ajay
authors.initials: A
authors.lastname: Abraham
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: R V
authors.initials: RV
authors.lastname: Shaji
authors.forename: Rayaz
authors.initials: R
authors.lastname: Ahmed
authors.forename: Aby
authors.initials: A
authors.lastname: Abraham
authors.forename: Biju
authors.initials: B
authors.lastname: George
authors.forename: Alok
authors.initials: A
authors.lastname: Srivastava
authors.forename: Mammen
authors.initials: M
authors.lastname: Chandy
authors.forename: Vikram
authors.initials: V
authors.lastname: Mathews
authors.forename: Poonkuzhali
authors.initials: P
authors.lastname: Balasubramanian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C531130:CBR3 protein, human; C000847:daunorubicinol; D003630:Daunorubicin