CBR3 reduces DOX to DOXOL

The anthracycline doxorubicin (DOX, adriamycin) is a widely-used chemotherapeutic agent effective against a broad range of malignant neoplasms, including blood cancers, carcinomas, and sarcomas. Its use is dose-limited by off-target complications, namely cardiomyopathies. Doxorubicinol (DOXOL, adriamycinol), an alcohol metabolite of doxorubicin, has been implicated in the cardiotoxicity observed in doxorubicin-treated patients (Olson et al. 1998). In a mouse model, carbonyl reductase [NADPH] 3 (Cbr3) is able to catalyse the NADPH-dependent two-electron reduction of DOX to DOXOL but at a much lower efficiency than its well-characterised family member Cbr1 (Schaupp et al. 2015). Naturally occurring variants of human CBR3 can significantly alter anthracycline metabolism (Bains et al. 2010). Inhibition of CBRs may provide protection from doxorubicinol cardiotoxicity.

蒽环类药物多柔比星（DOX，阿霉素）是一种广泛使用的化疗药物，对多种恶性肿瘤有效，包括血液癌、癌和肉瘤。其使用受到脱靶并发症的限制，即心肌病。多柔比星醇（DOXOL，阿霉素醇），是多柔比星的醇代谢产物，已被证实与接受多柔比星治疗患者观察到的心脏毒性有关（Olson 等，1998年）。在鼠模型中，羰基还原酶 [NADPH] 3（Cbr3）能够催化依赖于 NADPH 的两电子还原 DOX 至 DOXOL，但其效率远低于其已充分表征的家族成员 Cbr1（Schaupp 等，2015年）。人类 CBR3 的天然变异可以显著改变蒽环类药物的代谢（Bains 等，2010年）。抑制 CBRs 可能为防止多柔比星醇的心脏毒性提供保护。