CBR3 reduces DOX to DOXOL

Stable Identifier
R-HSA-8937419
Type
Reaction [transition]
Species
Homo sapiens
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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.

Literature References
PubMed ID Title Journal Year
2897122 Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol

Olson, RD, Mushlin, PS, Brenner, DE, Fleischer, S, Cusack, BJ, Chang, BK, Boucek, RJ

Proc. Natl. Acad. Sci. U.S.A. 1988
20007405 Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism

Bains, OS, Karkling, MJ, Lubieniecka, JM, Grigliatti, TA, Reid, RE, Riggs, KW

J. Pharmacol. Exp. Ther. 2010
25446851 Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3

Schaupp, CM, White, CC, Merrill, GF, Kavanagh, TJ

Chem. Biol. Interact. 2015
Participants
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Catalyst Activity
Catalyst Activity
Title
carbonyl reductase (NADPH) activity of CBR3 [cytosol]
Physical Entity
Activity
Orthologous Events
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Created