Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids

Abstract

Despite being the first conjugation reaction demonstrated in humans, amino acid conjugation as a route of metabolism of xenobiotic carboxylic acids is not well characterised. This is principally due to the small number and limited structural diversity of xenobiotic substrates for amino acid conjugation. Unlike CYP and uridine 5′-diphosphate glucuronosyltransferase, which are localised in the endoplasmic reticulum, the enzymes of amino acid conjugation reside in mitochondria. Unique among drug metabolism pathways, amino acid conjugation involves initial formation of a xenobiotic acyl-CoA thioester that is then conjugated principally with glycine in humans. However, formation of the xenobiotic acyl-CoA thioester does not always infer subsequent amino acid conjugation. Evidence is presented that in the absence of glycine conjugation substrates that form acyl-CoA thioesters perturb mitochondrial function. This review discusses literature on the enzymes involved and the concept that xenobiotic substrate selectivity provides a barrier to protect the metabolic integrity of the mitochondria.