Functional Characterization of the Promoter of Human Carbonyl Reductase 1 (CBR1). Role ofXREElements in Mediating the Induction ofCBR1by Ligands of the Aryl Hydrocarbon Receptor

Lakhman, Sukhwinder S.; Chen, Xiaomin; González-Covarrubias, Vanessa; Schuetz, Erin G.; Blanco, Javier G.

doi:10.1124/mol.107.035550

Cited by 35 publications

(34 citation statements)

References 34 publications

(37 reference statements)

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“…Alternatively, the CBR1 expression variability may reflect the individual induction status by xenobiotics. The human CBR1 promoter undergoes induction by xenobiotics, which is mediated by the aryl hydrocarbon receptor (Lakhman et al, 2007). Modulation of CBR1 expression by nongenetic factors would be consistent with the intraindividual differences in DOX pharmacokinetics observed in one third of patients treated with DOX at an interval of 4 weeks (Palle et al, 2006).…”

Section: Kassner Et Almentioning

confidence: 68%

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

Kassner¹,

Huse²,

Martin³

et al. 2008

Drug Metab Dispos

162

143

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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.

show abstract

Section: Kassner Et Almentioning

confidence: 68%

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

Kassner¹,

Huse²,

Martin³

et al. 2008

Drug Metab Dispos

162

143

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“…The transcription factor Nrf2 and the aryl hydrocarbon receptor ligand have been hypothesized to induce CBR1 (39). We previously showed that CBR1 is transcriptionally induced in response to hypoxia (40).…”

Section: Discussionmentioning

confidence: 99%

Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide

et al. 2012

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Arsenic trioxide (As 2 O 3 ) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As 2 O 3 in treating other leukemias have limited its wider use in therapeutic applications. In the present study, we found that the expression of carbonyl reductase 1 (CBR1) affects the resistance to As 2 O 3 in leukemias, including APL; As 2 O 3 upregulated CBR1 expression at the transcriptional level by stimulating the activity of the transcription factor activator protein-1. Moreover, CBR1 overexpression was sufficient to protect cells against As 2 O 3 through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As 2 O 3 . A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As 2 O 3 -induced apoptotic cell death compared with As 2 O 3 alone, both in vitro and in vivo. These results were confirmed in primary cultured human acute and chronic myeloid leukemia cells, with no significant cell death observed in normal leukocytes. Taken together, our findings indicate that CBR1 contributes to the low efficacy of As 2 O 3 and, therefore, is a rational target for the development of combination chemotherapy with As 2 O 3 in diverse leukemias including APL. Cancer Res; 72(16); 4214-24. Ó2012 AACR.

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“…Therefore, curcumin may also suppress the upregulation of NFkappaB regulated reductases, e.g. CBR1 [51].…”

Section: Discussionmentioning

confidence: 99%

Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – Carbonyl reductase 1

Hintzpeter¹,

Hornung²,

Ebert³

et al. 2015

Chemico-Biological Interactions

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Functional Characterization of the Promoter of Human Carbonyl Reductase 1 (CBR1). Role ofXREElements in Mediating the Induction ofCBR1by Ligands of the Aryl Hydrocarbon Receptor

Cited by 35 publications

References 34 publications

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

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

Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide

Curcumin is a tight-binding inhibitor of the most efficient human daunorubicin reductase – Carbonyl reductase 1

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