Synthesis and toxicity profile in 293 human embryonic kidney cells of the β D-glucuronide derivatives of <i>ortho</i>-<i>, meta</i>- and <i>para</i>-cresol

London, James A ORCID: 0000-0002-5823-7057, Wang, Emily CS, Barsukov, Igor L ORCID: 0000-0003-4406-9803, Yates, Edwin A ORCID: 0000-0001-9365-5433 and Stachulski, Andrew V (2021) Synthesis and toxicity profile in 293 human embryonic kidney cells of the β D-glucuronide derivatives of <i>ortho</i>-<i>, meta</i>- and <i>para</i>-cresol. CARBOHYDRATE RESEARCH, 499. 108225-.

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Abstract

The formation of β-glucuronides is a major route by which mammals detoxify and remove breakdown products, such as l-tyrosine, as well as many xenobiotics, from their systems. In humans, dietary l-tyrosine is broken down largely by the action of the anaerobic gut bacterium C. difficile to p-cresol, providing a competitive advantage in the gut microbiota. Ortho- (o-) and meta- (m-), cresols, also present in the environment, may share a common degradative pathway. Relatively little work has been done on cresyl glucuronides. Here, a direct synthesis of o-, m-, and p-cresyl β-D-glucuronides from methyl 1,2,3,4 tetra-O-acetyl-β-d-glucuronate and the respective cresol employing trimethylsilyltriflate as promoter is presented. The protected intermediates were hydrolysed using aqueous sodium carbonate to yield the cresyl β-glucuronides. The toxicities of the o-, m- and p-cresyl β-D-glucuronides were compared. All three were less toxic to HEK293 cells than their respective cresol precursors: toxicity followed the order o < m < p for Na⁺ salts and o < p < m for Ca²⁺ salts. The m-cresyl-glucuronide Ca²⁺ salt and p-cresyl-glucuronide Na⁺ salt reduced colony formation by 11% and 9% (v. 30% reduction from the aglycone) respectively, whereas o-cresyl-glucuronide (both Na⁺ and Ca²⁺ salts), mildly stimulated HEK293 cell growth.

Item Type:	Article
Uncontrolled Keywords:	beta-D-glucuronides, o-, m-, and p-cresol toxicity, Anaerobic gram-negative gut bacteria, Human embryonic kidney cells, L-tyrosine, C. difficile
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Science and Engineering > School of Physical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	01 Nov 2022 15:28
Last Modified:	09 Oct 2023 15:58
DOI:	10.1016/j.carres.2020.108225
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3128242