Autocatalytic modification of human carbonyl reductase by 2‐oxocarboxylic acids

Wermuth, Bendicht; Bohren, Kurt M.; Ernst, Elsbeth

doi:10.1016/0014-5793(93)80719-b

Cited by 25 publications

(29 citation statements)

References 13 publications

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“…The 10-fold discrepancy between both studies may be due in part to different strategies for CBR1 immunodetection. That is, Kassner et al (2008) performed electrophoretic separations by using 12% polyacrylamide gels, and CBR1 was detected as a triple band after immunoblotting due to the binding of 2-oxocarbonyl acids to lysine 239 (Wermuth et al, 1993;Kassner et al, 2008). We also found that hepatic doxorubicin reductase activity varied by 22-fold in samples from blacks and whites (Fig.…”

Section: Gonzalez-covarrubias Et Almentioning

confidence: 58%

Pharmacogenetics of Human Carbonyl Reductase 1 (CBR1) in Livers from Black and White Donors

González-Covarrubias

Zhang²,

Kalabus³

et al. 2009

Drug Metabolism and Disposition

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ABSTRACT:Carbonyl reductase 1 (CBR1) reduces the anticancer drug doxorubicin into the cardiotoxic metabolite doxorubicinol. We documented the hepatic expression of CBR1 in samples from white and black donors. Concordance between ethnicity and geographical ancestry was examined with ancestry informative markers. Livers from blacks and whites showed similar CBR1 mRNA levels (CBR1 mRNA blacks ‫؍‬ 4.8 ؎ 4.3 relative -fold versus CBR1 mRNA whites ‫؍‬ 3.6 ؎ 3.6 relative -fold; p ‫؍‬ 0.217). CBR1 protein levels did not differ between both groups (CBR1 blacks

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Section: Gonzalez-covarrubias Et Almentioning

confidence: 58%

Pharmacogenetics of Human Carbonyl Reductase 1 (CBR1) in Livers from Black and White Donors

González-Covarrubias

Zhang²,

Kalabus³

et al. 2009

Drug Metabolism and Disposition

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“…Finally, it was shown that the three isoforms, which show the same catalytic activity toward menadione (Bohren et al, 1987;Wermuth et al, 1993), result from covalent modifications of a lysine residue (Krook et al, 1993b;Wermuth et al, 1993;Sciotti et al, 2000). Forrest and coworkers first reported the occurrence of this modified lysine residue at position 239 of CBR1, although, at that time, the nature of the modification was not clarified (Forrest et al, 1990).…”

Section: Carbonyl Reductases In Mammalsmentioning

confidence: 95%

Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

Hoffmann¹,

Maser²

2007

Drug Metabolism Reviews

200

124

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Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent hydroxysteroid dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.

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“…4A) as a result of the binding of 2-oxocarbonyl acids such as pyruvate and 2-oxoglutarate to lysine 239. This modification reflects the metabolic state of the cell and has no apparent effect on CBR1 activity (Krook et al, 1993a,b;Wermuth et al, 1993). Western blot analysis of all three bands taken together revealed a large variability in CBR1 expression among cytosols from 80 human liver biopsies.…”

Section: Downloaded Frommentioning

confidence: 99%

Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver

Kassner¹,

Huse²,

Martin³

et al. 2008

Drug Metabolism and Disposition

165

146

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ABSTRACT:A first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent K m of ϳ140 M. Of six enzymes found to reduce DOX, K m values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency. However, inhibition constants for DOX reduction with 4-amino-1-tert-butyl-3-(2-hydroxyphenyl)pyrazolo[3,4-d]pyrimidine(an inhibitor that can discriminate between CBR1 and AKR1C3) were identical for CBR1 and human liver cytosol, but not for AKR1C3. These results suggest that CBR1 is a predominant hepatic DOX reductase. In cytosols from 80 human livers, the expression level of CBR1 and the activity of DOX reduction varied >70-and 22-fold, respectively, but showed no association with CBR1 gene variants found in these samples. Instead, the interindividual differences in CBR1 expression and activity may be mediated by environmental factors acting via recently identified xenobiotic response elements in the CBR1 promoter. The variability in the CBR1 expression may affect outcomes of therapies with DOX, as well as with other CBR1 substrates.

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Autocatalytic modification of human carbonyl reductase by 2‐oxocarboxylic acids

Cited by 25 publications

References 13 publications

Pharmacogenetics of Human Carbonyl Reductase 1 (CBR1) in Livers from Black and White Donors

Pharmacogenetics of Human Carbonyl Reductase 1 (CBR1) in Livers from Black and White Donors

Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver

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