Expression of the anthracycline-metabolizing enzyme carbonyl reductase 1 in hearts from donors with Down syndrome.
Cancer patients with Down syndrome (DS) are susceptible to developing anthracycline-related cardiotoxicity. The pathogenesis of anthracycline-related cardiotoxicity has been linked to the intracardiac synthesis of alcohol metabolites by carbonyl reductase 1 (CBR1). CBR1 is located in the DS critical region (21q22.12). The expression of CBR1 in hearts from individuals with DS has not been characterized. This study documented CBR1 expression in hearts from donors with DS (n = 4) and donors without DS (n = 15). The DS samples showed 1.8-fold higher CBR1 mRNA levels compared to the non-DS samples (levels in DS samples were 3.3-relative fold, and those in non-DS were 1.8-relative fold; p = 0.012). CBR1 protein levels were 1.9-fold higher in DS samples than in non-DS samples (13.5 ± 7.7 versus 7.2 ± 3.9 nmol/g cytosolic protein, respectively; p = 0.029). CBR1 activity for daunorubicin was 1.7-fold higher in DS samples than in non-DS samples (3.8 ± 0.1 versus 2.3 ± 0.2 nmol daunol/min · mg, respectively; p = 0.050). CBR1 1096G>A (rs9024) affects CBR1 activity, and one heart trisomic for the variant A allele (A/A/A) exhibited low enzymatic activity. These findings suggest that increased CBR1 expression in the hearts of individuals with DS may contribute to the risk of anthracycline-related cardiotoxicity.
Kalabus
James L
JL
Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, NY 14260, USA.
Sanborn
Carrie C
CC
Jamil
Raqeeb G
RG
Cheng
Qiuying
Q
Blanco
Javier G
JG
D000429:Alcohol Oxidoreductases / Q000235:genetics*; D018943:Anthracyclines / Q000378:metabolism* / Q000633:toxicity; D004314:Down Syndrome / Q000201:enzymology*; D005838:Genotype; D006321:Heart / Q000187:drug effects; D006801:Humans; D009206:Myocardium / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D014019:Tissue Donors
D018943:Anthracyclines; D012333:RNA, Messenger; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human