ROLE OF HEPATIC FATTY ACID:COENZYME A LIGASES IN THE METABOLISM OF XENOBIOTIC CARBOXYLIC ACIDS

SUMMARY 1. Formation of acyl‐coenzymes (Co)A occurs as an obligatory step in the metabolism of a variety of endogenous substrates, including fatty acids. The reaction is catalysed by ATP‐dependent acid:CoA ligases (EC 6.2.1.1‐2.1.3; AMP forming), classified on the basis of their ability to conjugate saturated fatty acids of differing chain lengths, short (C2‐C4), medium (C4‐C12) and long (C10‐C22). The enzymes are located in various cell compartments (cytosol, smooth endoplasmic reticulum, mitochondria and peroxisomes) and exhibit wide tissue distribution, with highest activity associated with liver and adipose tissue. 2. Formation of acyl‐CoA is not unique to endogenous substrates, but also occurs as an obligatory step in the metabolism of some xenobiotic carboxylic acids. The mitochondrial medium‐chain CoA ligase is principally associated with metabolism via amino acid conjugation and activates substrates such as benzoic and salicylic acids. Although amino acid conjugation was previously considered an a priori route of metabolism for xenobiotic‐CoA, it is now recognized that these highly reactive and potentially toxic intermediates function as alternative substrates in pathways of intermediary metabolism, particularly those associated with lipid biosyntheses. 3. In addition to a role in fatty acid metabolism, the hepatic microsomal and peroxisomal long‐chain‐CoA‐ligases have been implicated in the formation of the acyl‐CoA thioesters of a variety of hypolipidaemic and peroxisome proliferating agents (e.g. cloflbric acid) and of the r(‐)‐enantiomers of the commonly used 2‐arylpropionic acid non‐steroidal anti‐inflammatory drugs (e.g. ibuprofen). In vitro kinetic studies using rat hepatic microsomes and peroxisomes have alluded to the possibility of xenobiotic‐CoA ligase multiplicity. Although cDNA encoding a long‐chain ligase have been isolated from rat and human liver, there is currently no molecular evidence of multiple isoforms. The gene has been localized to chromosome 4 and homology searches have revealed a significant similarity with enzymes of the luciferase family. 4. Increasing recognition that formation of a CoA conjugate increases chemical reactivity of xenobiotic carboxylic acids has led to an awareness that the relative activity, substrate specificity and intracellular location of the xenobiotic‐CoA ligases may explain differences in toxicity. 5. Continued characterization of the human xenobiotic‐CoA ligases in terms of substrate/inhibitor pr