The role of carbonyl reductase 1 in drug discovery and development

ABSTRACT

Introduction: Carbonyl reductase 1 (CBR1) plays a critical role in drug metabolism of ketones and aldehydes. CBR1 has broad substrate specificity and is involved in metabolizing a number of clinically important drugs.

Areas covered: The impact of CBR1 in drug metabolism and disposition are discussed. The CBR1 enzyme is covered in detail including discussion on topics such as tissue distribution, species difference, individual variability, the effect of genetic polymorphism and disease state, inducibility and drug-drug interaction potential. The structure and function of CBR1 and CBR3 are also compared. In addition, the formation of chiral alcohols from CBR1 reduction and MIST coverage are reviewed.

Expert Opinion: As CBR1 is an emerging enzyme in drug discovery and development, much research is needed to further understand its role in drug metabolism and disposition. In vitro-in vivo correlation for CBR1-mediated clearance is mostly unknown. Selective CBR1 inhibitors and substrates are not well enough characterized for reaction phenotyping of the CBR1 pathway. Multiple pathways appear to be involved in the regulation of CBR1. Future investigation will also help reveal their impact on drug-drug interaction potentials and the influence of individual variability.

KEYWORDS:

• Carbonyl reductase 1
• metabolism
• tissue distribution
• induction
• genetic polymorphism
• species difference

Article highlights

• CBR1 has broad substrate specificity and can reduce a wide range of carbonyl containing compounds.

• CBR1 is ubiquitously distributed in human tissues with high expression in intestine, liver and kidney. Significant species differences in tissue distribution have been observed.

• High individual variability of CBR1 has been reported: 13–48 fold based on mRNA, 4–9 fold based on protein expression and 22 fold based on reductase activity.

• CBR1 is inducible through AHR, Nfr2, HIF-1α, AP-1 and PPARα, with AHR pathway being most studied. Drug-drug interaction risk is low for CBR1, but should not be overlooked.

• CBR1-mediated reduction tends to be stereo-selective to form chiral metabolites. MIST coverage should be evaluated as species differences in stereo-selectivity can occur.

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Acknowledgements

The authors thank Jean-Claude Marshall, Hong Wu, William Mounts, Hugo Berube and Wen He for their help and useful discussion; A. David Rodrigues for providing literature references; Larry Tremaine and Tess Wilson for their leadership and support.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded