Formation of hybrid triacylglycerides and cholesteryl esters

Incorporation of xenobiotic acids into lipids forms highly lipophilic metabolites that may burden the body as long-retained residues. In the majority of cases, cholesterol esters or triacylglycerol analogs are formed. Candidate enzymes for such reactions are respectively:

• sterol O-acyltransferase (EC 2.3.1.26; acyl coenzyme A-cholesterol-O-acyltransferase, ACAT);

• diacylglycerol O-acyltransferase (EC 2.3.1.20); and

• 2-acylglycerol O-acyltransferase (EC 2.3.1.22) and other O-acyltransferases.

Some phospholipid analogs, as well as some esters to the 3-hydroxy group of biliary acids, have also been characterized.4,106

The number of drugs and other xenobiotics known to form glyceryl or cholesteryl esters is currently limited. To the best of our knowledge, only a few nonmedicinal xenobiotics but no drugs have been reported to form cholesteryl esters (reaction D in Figure 19). In contrast, results are accumulating on many acidic drugs and other xenobiotics forming triacylglycerol analogs, also called hybrid triglycerides (reaction E in Figure 19).107 One telling example is that of ibuprofen (62, Figure 20; see Section 5.06.3.6.4), a much used NSAID whose (R)-enantiomer forms hybrid triglycerides detectable in rat liver and in human and rat adipose tissues.100 A similar formation of hybrid triglycerides has been reported for, e.g., the NSAID ketoprofen (43, Figure 16) and the antihyperlipidemic agent lifibrol (63, Figure 20).108 The covalent incorporation of valproic acid (44 in Figure 16 and Figure 21) into phospholipids in neurons is also of note.109

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