The significance of xenobiotic-lipid conjugation.

It is also likely that the formation of certain of the metabolites described above would be associated with changes in lipid and/or fatty acid metabolism, either by depleting the tissues of an essential intermediate or by disturbance of the normal allosteric and feedback regulation of lipid synthesis and catabolism. Although very little is known about the possible biochemical mechanisms of these processes, it appears likely that the formation of many of the novel metabolites of carboxylic acids involves their acyl-CoA thioesters (Caldwell, 1984). The potential of these to disrupt normal lipid metabolism is considerable (Sherratt, 1985). The normal functioning of living cells depends to a large extent upon normal function of various membranes. Lipidrelated xenobiotic conjugates, notably the hybrid triglycerides and the cholesteryl esters, have the potential to enter membranes and alter membrane structure by their steric effects. This could in turn modify membranedependent processes, either by altered structure or by slowing the deacylation-reacylation cycling of fatty acid residues within the membrane. It is of particular interest to note that the formation of the cholesteryl ester of IPCA after the administration of fenvalerate is apparently responsible for the granulomatous changes seen in the liver and certain other organs. The granulomas contain the cholesteryl ester in high concentration, and administration of the synthetic ester at a dose of 10mg/kg for as short a time as 7 days resulted in the appearance of granulomas in mouse liver (Miyamoto et al., 1985). In conclusion, it is clear that the application of modern analytical techniques to tissue residues of xenobiotics and to highly non-polar metabolites in the excreta has succeeded in revealing the occurrence of new types of conjugates, related in various ways to processes of lipid biochemstry. At the present time, the significance of these various types of reactions lies very much in the area of speculation. However, in view of toxicological concern about many compounds which give rise to these novel metabolites, and the failure of ‘conventional’ metabolic studies to shed light upon such problems, it is important that the potential implications of these reactions be borne in mind in such cases.