Clinical implications of genetic variation in carboxylesterase drug metabolism

ABSTRACT

Introduction: Mammalian carboxylesterase enzymes are a highly conserved metabolic pathway involved in the metabolism of endogenous and exogenous compounds including many widely prescribed therapeutic agents. Recent advances in our understanding of genetic polymorphisms affecting enzyme activity have exposed potential therapeutic implications.

Areas covered: The aims of this review are to provide an overview of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) gene structure, to summarize the known polymorphism affecting substrate-drug metabolism, and to assess the potential therapeutic implications of genetic variations affecting enzyme function.

Expert opinion: Genetic variability in carboxylesterase drug metabolism is a nascent area of research with only a handful of the thousands of SNPs investigated for their potential effects of enzyme activity or carboxylesterase-substrate disposition and therapeutics. It remains to be determined if the wide variability in enzyme activity can be explained by genetic variation, and used in personalized medicine to improve clinical outcomes.

KEYWORDS:

• Carboxylesterase
• CES1
• CES2
• drug metabolism
• pharmacogenetics
• single-nucleotide polymorphism

Article highlights

• A number of carboxylesterase drugs have very low therapeutic indexes (e.g., clopidogrel, dabigatran etexilate, capecitabine, irinotecan)

• Haplotype and diplotype genotypes, as well as functional CES1 gene copy number influence transcription and expression.

• Thousands of genetic polymorphisms are documented, but only a small proportion have been profiled.

• CES1 SNPs shown to affect enzyme activity are loss-of-function variants.

• No CES2 SNPs have been shown to alter enzyme activity, but a number are associated with changes in drug disposition and clinical outcomes.

• Determining the role of carboxylesterase SNPs in personalized medicine will require further advances in the field.

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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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.