CBR3 reduces DOX to DOXOL

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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
20007405 Naturally occurring variants of human CBR3 alter anthracycline in vitro metabolism

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

J. Pharmacol. Exp. Ther. 2010
2897122 Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol

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

Proc. Natl. Acad. Sci. U.S.A. 1988
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

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

Chem. Biol. Interact. 2015
Catalyst Activity

carbonyl reductase (NADPH) activity of CBR3 [cytosol]

Orthologous Events
Cite Us!