Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, NY 14260, USA.
Drug Metab Dispos. 2010 Dec;38(12):2096-9. doi: 10.1124/dmd.110.035550. Epub 2010 Aug 20.
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.
唐氏综合征（Down syndrome，DS）患者易发生蒽环类药物相关性心脏毒性。蒽环类药物相关性心脏毒性的发病机制与细胞色素 P450 还原酶 1（carbonyl reductase 1，CBR1）在内心脏合成酒精代谢物有关。CBR1 位于 DS 关键区域（21q22.12）。DS 个体心脏中 CBR1 的表达尚未得到描述。本研究记录了来自 DS 供体（n = 4）和非 DS 供体（n = 15）心脏的 CBR1 表达。DS 样本的 CBR1 mRNA 水平比非 DS 样本高 1.8 倍（DS 样本的水平为 3.3 相对倍数，非 DS 样本为 1.8 相对倍数；p = 0.012）。DS 样本的 CBR1 蛋白水平比非 DS 样本高 1.9 倍（分别为 13.5 ± 7.7 和 7.2 ± 3.9 nmol/g 胞浆蛋白；p = 0.029）。DS 样本中 daunorubicin 的 CBR1 活性比非 DS 样本高 1.7 倍（分别为 3.8 ± 0.1 和 2.3 ± 0.2 nmol daunol/min·mg；p = 0.050）。CBR1 1096G>A（rs9024）影响 CBR1 活性，一个携带变异 A 等位基因（A/A/A）的心脏三体显示出低酶活性。这些发现表明，DS 个体心脏中 CBR1 表达增加可能导致蒽环类药物相关性心脏毒性的风险增加。
