Reactome | CBR3 reduces DOX to DOXOL

CBR3 reduces DOX to DOXOL

Stable Identifier

R-HSA-8937419

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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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
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
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
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