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Xenobiotica
the fate of foreign compounds in biological systems
Volume 52, 2022 - Issue 7
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General Xenobiochemistry

Species differences in liver microsomal hydrolysis of acyl glucuronide in humans and rats

, , , , ORCID Icon &
Pages 653-660 | Received 06 Aug 2022, Accepted 29 Sep 2022, Published online: 10 Oct 2022
 

Abstract

  1. Acyl glucuronides (AGs) are known as one of the causes of idiosyncratic drug toxicity (IDT). Although AGs can be enzymatically hydrolysed by β-glucuronidase and esterase, much information on their characteristics and species differences is lacking. This study was aimed to clarify species differences in AG hydrolysis between human and rat liver microsomes (HLM and RLM).

  2. To evaluate the AG hydrolysis profile, and the contribution of β-glucuronidase and esterase towards AG hydrolysis in HLM and RLM, nonsteroidal anti-inflammatory drugs (NSAIDs) were used. AGs were incubated with 0.1 M Tris-HCl buffer (pH 7.4) and 0.3 mg/mL HLM or RLM in the absence or presence of β-glucuronidase inhibitor, D-saccharic acid 1,4-lactone (D-SL) and esterase inhibitor, phenylmethylsulfonyl fluoride (PMSF).

  3. AGs of mefenamic acid (MEF-AG) and etodolac (ETO-AG) showed significantly higher AG hydrolysis rates in RLM than in HLM. Esterases were found to serve as AG hydrolases dominantly in HLM, whereas both esterases and β-glucuronidase equally contribute to AG hydrolysis in RLM. However, MEF-AG and ETO-AG were hydrolysed only by β-glucuronidase.

  4. We demonstrated for the first time that the activity of AG hydrolases towards NSAID-AGs differs between humans and rats.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by the Antiaging Project in Kindai University.

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