title: Interindividual variability in the cardiac expression of anthracycline reductases in donors with and without Down syndrome.
abstract: OBJECTIVE
  The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS.
  
  
  METHODS
  Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression.
  
  
  RESULTS
  CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts.
  
  
  CONCLUSIONS
  CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.
authors.affiliation: Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Quiñones-Lombraña
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferguson
authors.forename: Rachael
authors.initials: R
authors.lastname: Hageman Blair
authors.forename: James L
authors.initials: JL
authors.lastname: Kalabus
authors.forename: Almedina
authors.initials: A
authors.lastname: Redzematovic
authors.forename: Javier G
authors.initials: JG
authors.lastname: Blanco
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000449:Aldehyde Reductase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D018943:Anthracyclines / Q000009:adverse effects / Q000378:metabolism*; D054715:Cardiotoxins / Q000009:adverse effects / Q000378:metabolism; D003630:Daunorubicin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism; D004314:Down Syndrome / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
chemical_list: D018943:Anthracyclines; D054715:Cardiotoxins; D012333:RNA, Messenger; D015096:3-Hydroxysteroid Dehydrogenases; D000429:Alcohol Oxidoreductases; D006911:Hydroxyprostaglandin Dehydrogenases; D000449:Aldehyde Reductase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C000847:daunorubicinol; D003630:Daunorubicin