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Identification of the Promoter of Human Carbonyl Reductase 3 (CBR3) and Impact of Common Promoter Polymorphisms on Hepatic CBR3 mRNA Expression

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Abstract

Purpose

Recent studies suggest that polymorphisms in human carbonyl reductase 3 (CBR3) influence the pharmacodynamics of doxorubicin. First, we sought to identify the promoter of CBR3. Next, we examined whether two CBR3 promoter polymorphisms (CBR3 -725T>C and CBR3 -326T>A) dictate promoter activity and hepatic CBR3 mRNA levels.

Methods

The promoter activities of CBR3 reporter constructs were investigated in HepG2 and MCF-7 cells. CBR3 mRNA levels were documented in 95 liver samples from white (n = 62) and black (n = 33) donors. Genotype-phenotype correlation analyses were used to determine the impact of the CBR3 -725T>C and CBR3 -326T>A polymorphisms on hepatic CBR3 mRNA levels.

Results

We identified the promoter of human CBR3. Liver samples from black donors showed higher relative CBR3 mRNA levels than samples from whites (CBR3 mRNAblacks = 3.0 ± 3.1 relative fold vs. CBR3 mRNAwhites = 1.6 ± 1.5 relative fold, p = 0.021). The variant -725C and -326A alleles did not modify the gene reporter activities of engineered CBR3 promoter constructs. In line, hepatic CBR3 mRNA levels were not associated with CBR3 -725T>C and CBR3 -326T>A genotype status.

Conclusions

These studies provide the first insights into the regulation and variable hepatic expression of polymorphic CBR3.

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Abbreviations

AHR:

aryl hydrocarbon receptor

AIM:

ancestry informative markers

AP1 or JUN:

activator protein 1

CBR1 :

Carbonyl reductase 1

CBR3 :

Carbonyl Reductase 3

CBR4 :

Carbonyl reductase 4

CHF:

congestive heart failure

CI:

confidence interval

OCT-1 or POU2F1:

octamer binding transcription factor 1

PCR:

polymerase chain reaction

SNP:

single nucleotide polymorphism

SP1:

Sp1 transcription factor

XRE:

xenobiotic response elements

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ACKNOWLEDGEMENTS

The technical assistance of Erick Vasquez and Sukhwinder Lakhman is gratefully acknowledged.

This work was supported by NIH/NIGMS grant GM73646 to JGB. Genotype and phenotype datasets will be available at the PharmGKB database (http://www.pharmgkb.org).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, New York, 14260-1200, USA

    Jianping Zhang & Javier G. Blanco

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  1. Jianping Zhang
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  2. Javier G. Blanco
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Correspondence to Javier G. Blanco.

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Zhang, J., Blanco, J.G. Identification of the Promoter of Human Carbonyl Reductase 3 (CBR3) and Impact of Common Promoter Polymorphisms on Hepatic CBR3 mRNA Expression. Pharm Res 26, 2209–2215 (2009). https://doi.org/10.1007/s11095-009-9936-9

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  • DOI: https://doi.org/10.1007/s11095-009-9936-9

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