2015
DOI: 10.1124/dmd.115.064295
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Characterization of the Canine Anthracycline-Metabolizing Enzyme Carbonyl Reductase 1 (cbr1) and the Functional Isoform cbr1 V218

Abstract: The anthracyclines doxorubicin and daunorubicin are used in the treatment of various human and canine cancers, but anthracyclinerelated cardiotoxicity limits their clinical utility. The formation of anthracycline C-13 alcohol metabolites (e.g., doxorubicinol and daunorubicinol) contributes to the development of anthracyclinerelated cardiotoxicity. The enzymes responsible for the synthesis of anthracycline C-13 alcohol metabolites in canines remain to be elucidated. We hypothesized that canine carbonyl reductas… Show more

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Cited by 4 publications
(3 citation statements)
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“…The involvement of secondary alcohol metabolites in anthracyclineinduced cardiomyopathy is indicated by the evidence presented in several biochemical, pharmacokinetic, and genetic studies (Minotti et al, 2004;Salvatorelli et al, 2006;Gianni et al, 2008;Mordente et al, 2009;Ferguson et al, 2015). Anthracycline alcohol metabolite formation is catalyzed mainly by distinct cytosolic NADPH-dependent oxidoreductases (Mordente et al, 2003;Jin and Penning, 2007;Oppermann, 2007;Bains et al, 2010;Malátková et al, 2010;Blanco et al, 2012) that metabolize a broad range of endogenous and exogenous carbonyl-containing compounds, including steroids, eicosanoids, cofactors, neurotransmitters, and polyols (Jin and Penning, 2007;Oppermann, 2007;Bains et al, 2010;Malátková et al, 2010).…”
Section: Introductionmentioning
confidence: 99%
“…The involvement of secondary alcohol metabolites in anthracyclineinduced cardiomyopathy is indicated by the evidence presented in several biochemical, pharmacokinetic, and genetic studies (Minotti et al, 2004;Salvatorelli et al, 2006;Gianni et al, 2008;Mordente et al, 2009;Ferguson et al, 2015). Anthracycline alcohol metabolite formation is catalyzed mainly by distinct cytosolic NADPH-dependent oxidoreductases (Mordente et al, 2003;Jin and Penning, 2007;Oppermann, 2007;Bains et al, 2010;Malátková et al, 2010;Blanco et al, 2012) that metabolize a broad range of endogenous and exogenous carbonyl-containing compounds, including steroids, eicosanoids, cofactors, neurotransmitters, and polyols (Jin and Penning, 2007;Oppermann, 2007;Bains et al, 2010;Malátková et al, 2010).…”
Section: Introductionmentioning
confidence: 99%
“…Studies are warranted to examine whether inter-breed variability in the number of Sp1 motifs in concert with polymorphic cbr1 variants that influence enzymatic activity (i.e. the functional cbr1 D218V non-synonymous polymorphism) impact the pharmacodynamics of anthracyclines in canine patients (Ferguson et al, 2015). During the mapping of the canine cbr1 locus, we identified a conserved xenobiotic response element ( XRE, 5′-CACGCCA-3′) in the vicinity of the Sp1 cluster (~ 306 bp upstream of the translation initiation codon, A +1 TG) (Cheng et al, 2012).…”
Section: Discussionmentioning
confidence: 99%
“…Enzyme kinetics studies with recombinant canine cbr1 showed that “wild-type” cbr1 (i.e. cbr1 D218) and the variant isoform cbr1 V218 are capable of catalyzing the NADPH-dependent reduction of daunorubicin into its corresponding C-13 alcohol metabolite (Ferguson et al, 2015). There is a paucity of data describing the catalytic properties of the homologous canine cbr3.…”
Section: Introductionmentioning
confidence: 99%