The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?

  title={The Role of Human Carboxylesterases in Drug Metabolism: Have We Overlooked Their Importance?},
  author={S. Casey Laizure and Vanessa L. Herring and Zheyi Hu and Kevin Witbrodt and Robert B. Parker},
  journal={Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy},
Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance… 

The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

  • L. Di
  • Biology, Medicine
    Current drug metabolism
  • 2019
CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life, although they should not be overlooked, particularly interaction with alcohols.

Clinical implications of genetic variation in carboxylesterase drug metabolism

An overview of carboxylesterase 1 and carboxyleterase 2 gene structure is provided to summarize the known polymorphism affecting substrate-drug metabolism, and the potential therapeutic implications of genetic variations affecting enzyme function are assessed.

Major implications of single nucleotide polymorphisms in human carboxylesterase 1 on substrate bioavailability.

Details provided in this review could give a clear-cut idea or information that could be used for further studies regarding the safety and efficacy of CES1 substrate.

Effects of Alcohol on Human Carboxylesterase Drug Metabolism

The results suggest that alcohol’s inhibition of CES1 could potentially result in clinically significant drug interactions with other CES1-substrate drugs, but it is unlikely to significantly affect CES2- Substrate drug hydrolysis.

Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction

The catalytic mechanism of hCES1 is studied by the quantum mechanics computation method and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of h CES1 substrates and drug designing.

Effect of Disease State on Human Carboxylesterase 1 Expression and Activity

The data showed that diabetic subjects had less CES1 hydrolytic efficiency and African American group had significantly higher CES1 activity as compared to Caucasian group, which provides potential explanation to the clinical observation that African Americans subjects exhibit higher resistance to the CES1 substrates clopidogrel.



The mammalian carboxylesterases: from molecules to functions.

A comparison of the nucleotide and amino acid sequence of the mammalian carboxylesterases shows that all forms expressed in the rat can be assigned to one of three gene subfamilies with structural identities of more than 70% within each subfamily.

Human carboxylesterase 1: from drug metabolism to drug discovery.

The crystal structures of hCE1 in complex with either the cocaine analogue homatropine or the heroin analogue naloxone are determined, the first structures of a human carboxylesterase, and they provide details about narcotic metabolism in humans.

Clinical Significance of Esterases in Man

The concentration of aspirin relative to salicylate in the circulation may be affected by individual variation in esterase levels and the relative roles of the different esterases, and this may influence the overall pharmacological effect.

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

  • M. RossJ. Crow
  • Biology
    Journal of biochemical and molecular toxicology
  • 2007
The hydrolytic activity of individual HLMs toward bioresmethrin and procaine did not correlate with the protein content of hCE1 and hCE2, so the mere abundance of CE proteins is not a good predictor of CE activity in HLMs.

Human carboxylesterase isozymes: catalytic properties and rational drug design.

  • T. Imai
  • Biology
    Drug metabolism and pharmacokinetics
  • 2006
The expression pattern of CES in Caco-2 cell monolayer, a useful in vitro model for rapid screening of human intestinal drug absorption, is completely different from that in human small intestine but very similar to human liver that expresses a much higher level of hCE-1 and lower level ofhCE-2.

Nuclear receptor-mediated regulation of carboxylesterase expression and activity

This review summarizes the current state of knowledge regarding NR-mediated regulation of CES enzymes in mammals and highlights their importance in drug metabolism, drug–drug interactions and toxicology.

Inter-individual variability in esterases in human liver.