Carboxylesterase Function and Drug Metabolism

Carboxylesterases are a family of α/β-hydrolase enzymes that catalyse the hydrolysis of ester- and amide-based substrates, representing a key step in the biotransformation of a broad range of xenobiotics and endogenous compounds. Predominantly expressed in liver and intestine, these isozymes mediate first-pass metabolism, influencing oral bioavailability, systemic clearance and the activation of prodrugs into their pharmacologically active forms. Differential tissue distribution and substrate specificity among major human isozymes, CES1 and CES2, underlie variations in drug efficacy and toxicity, while genetic polymorphisms can further modulate enzyme activity and therapeutic outcomes. Beyond drug metabolism, carboxylesterases participate in lipid homeostasis by regulating intracellular lipid droplet turnover and influencing energy balance. Advances in structural biology have elucidated key active-site residues and conformational dynamics that determine substrate selectivity, guiding the rational design of novel prodrugs and isozyme-selective inhibitors. Clinically, modulation of carboxylesterase activity has emerged as a strategy to optimise pharmacokinetics, mitigate adverse effects and personalise treatment regimens, with translational studies in humanised animal models and innovative imaging probes propelling this field towards precision medicine.

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Carboxylesterase Function and Drug Metabolism publication trend

The graph below shows the total number of articles in carboxylesterase function and drug metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Carboxylesterase (CE): An enzyme that hydrolyses ester or amide bonds in small molecules, crucial for drug metabolism.

First-pass metabolism: The initial enzymatic modification of orally administered compounds in the intestine and liver before systemic circulation.

Prodrug: An inactive precursor that requires enzymatic conversion to generate an active pharmacological agent.

Isozyme: One of several enzyme variants within the same family that catalyse identical reactions but differ in structure, tissue distribution and substrate specificity.

Hydrolysis: A chemical reaction in which water cleaves bonds in substrates, often mediated by hydrolase enzymes to facilitate drug clearance.

References

1. Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice. Acta Pharmacologica Sinica (2024).
2. Ferrocene-chalcone-based probe for the fluorescence and electrochemical dual-mode detection of carboxylesterase. Sensors and Actuators B Chemical (2024).
3. Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs. Molecules (2008).
4. Carboxylesterases in lipid metabolism: from mouse to human. Protein & Cell (2017).