Pharmacogenetics of aldo-keto reductase 1C (AKR1C) enzymes

ABSTRACT

Introduction: Genetic variation in metabolizing enzymes contributes to variable drug response and disease risk. Aldo-keto reductase type 1C (AKR1C) comprises a sub-family of reductase enzymes that play critical roles in the biotransformation of various drug substrates and endogenous compounds such as steroids. Several single nucleotide polymorphisms have been reported among AKR1C encoding genes, which may affect the functional expression of the enzymes.

Areas covered: This review highlights and comprehensively discusses previous pharmacogenetic reports that have examined genetic variations in AKR1C and their association with disease development, drug disposition, and therapeutic outcomes. The article also provides information about the effect of AKR1C genetic variants on enzyme function in vitro.

Expert opinion: The current evidence that links the effect of AKR1C gene polymorphisms to disease progression and development is inconsistent and needs further validation, despite of the tremendous knowledge available. Information about association of AKR1C genetic variants and drug efficacy, safety, and pharmacokinetics is limited, thus, future studies that advance our understanding about these relationships and their clinical relevance are needed. It is imperative to achieve consistent findings before the potential translation and adoption of AKR1C genetic variants in clinical practice.

KEYWORDS:

• Metabolism
• aldo-keto reductase 1C
• pharmacogenetics
• single nucleotide polymorphism
• disease susceptibility
• treatment outcome

Article highlights

• Reduction mediated by reductase enzymes contributes to the metabolism of a significant number of biological substrates and drugs.

• Genes encoding for aldo-keto reductase 1C isoforms are polymorphic.

• In-vitro studies indicate that multiple genetic variations of AKR1C decrease the activities of the corresponding enzymes.

• Association studies have shown that single nucleotide polymorphisms of AKR1C genes could be associated with disease development such as cancer, although these associations are controversial.

• Limited and conflicted evidence exists about the effect of AKR1C gene variations on drug outcomes, which is limited to anthracycline therapy.

• It is essential to further clarify the effect of various AKR1C genetic variants on drug disposition and therapeutic outcomes by conducting well-designed prospective studies.

This box summarizes key points contained in the article.

Acknowledgements

The author is very thankful to Dr. Bradley Urquhart, University of Western Ontario for his critical review of the manuscript.

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.