The emerging role of human esterases.
In this review, novel aspects of the role of esterases, which contribute to the metabolism of 10% of therapeutic drugs, are described. Esterases hydrolyze the compounds that contain ester, amide, and thioester bonds, which cause prodrug activation or detoxification. Among esterases, carboxylesterases are well known to be involved in the hydrolysis of a variety of drugs. Additionally, other esterases have recently received attention for their pharmacological and toxicological roles. Arylacetamide deacetylase (AADAC) is involved in the hydrolysis of flutamide, phenacetin, and rifamycins. AADAC is associated with adverse drug reactions because the hydrolytic metabolites of flutamide and phenacetin appear to be associated with hepatotoxicity and nephrotoxicity/hematotoxicity, respectively. Paraoxonase and butyrylcholinesterase hydrolyze pirocarpine/simvastatin and succinylcholine/bambuterol, respectively. Although the esterases that hydrolyze the acyl-glucuronides of drugs have largely been unknown, we recently found that α/β hydrolase domain containing 10 (ABHD10) is responsible for the hydrolysis of mycophenolic acid acyl-glucuronide in human liver. Because acyl-glucuronides are associated with toxicity, ABHD10 might function as a detoxification enzyme. Thus, various esterases, which include enzymes that have not been known to hydrolyze drugs, are involved in drug metabolism with different substrate specificity. Further esterase studies should be conducted to promote our understanding in clinical pharmacotherapy and drug development.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan. tatsuki@p.kanazawa-u.ac.jp
Tatsuki
T
Fukami
Tsuyoshi
T
Yokoi
D000818:Animals; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D010599:Pharmacokinetics; D011355:Prodrugs / Q000493:pharmacokinetics*
D011355:Prodrugs; D004950:Esterases