Toxicological significance of novel esterases involved in the hydrolysis of acyl-glucuronides

通常，含有羧酸的药物在体内代谢为酰基-葡糖苷酸（AG）形式，被认为会引起各种毒性，包括肝毒性和过敏反应。因此，可以想象水解AG的酶可以减弱药物诱导的毒性。在这项研究中，负责AG水解的酶进行了鉴定，并阐明了其功能。通过从人肝脏中纯化，α/β水解酶结构域包含10（ABHD 10）被鉴定为AG水解酶。ABHD 10可水解多种AG，如霉酚酸、丙磺舒和双氯芬酸的AG。对于体内研究，经口给予双氯芬酸后，与未处理小鼠相比，ABHD 10抑制剂预处理小鼠的AG血浆浓度显著更高。 因此，阐明了在体内ABHD 10可以影响AG的血浆浓度。 ABHD 10可能在减轻AGs诱导的毒性中起重要作用。

In general, drugs containing carboxylic acid are metabolized to acyl-glucuronide (AG) forms, which are considered to cause various toxicities including hepatotoxicity and anaphylaxis, in body. Therefore, it is conceivable that the enzymes hydrolyzing AG can attenuate the drug-induced toxicities. In this study, the enzyme responsible for AG hydrolysis was identified and its function was clarified. By the purification from human livers, alpha/beta hydrolase domain containing 10 (ABHD10) was identified as an AG hydrolase. ABHD10 could hydrolyze various kinds of AG such as AGs of mycophenolic acid, probenecid, and diclofenac. For in vivo study, mice pre-treated with an ABHD10 inhibitor showed the significantly higher AG plasma concentration compared with non-treated mice after an oral administration of diclofenac. Thus, it was clarified in vivo that ABHD10 can affect the plasma concentration of AGs. ABHD10 may play important roles for attenuation of the AGs-induced toxicity.