N

The xenobiotic substrates of acetylation (box in Figure 17) are mainly primary amines of medium basicity, namely arylamines, hydrazines (R = H or aryl), and hydrazides (R = COR'). Medicinal examples include pra-aminosalicylic acid (51, Figure 18), sulfamethazine (52) and first-generation sulfonamides, isoniazid (53) and hydralazine (54). Xenobiotics of toxicological interest include hydrazine itself, and many carcinogenic arylamines such as benzidine. Few basic primary amines of medicinal interest have been reported to form N-acetylated metabolites, but a noteworthy recent example is that of trovafloxacin (35, Figure 13; R = H). Human volunteers who had been given the drug excreted it partly unchanged and partly as the sulfamate (see Section 5.06.3.3.2), the acyl-glucuronide (the major circulating metabolite), and the N-acetyl conjugate (35, Figure 13; R = COCH3), which accounted for about 6% of the dose. 67

Xenobiotic arylhydroxylamines can also be acetylated, but the reaction is one of O-acetylation (box in Figure 17). This is the reaction formally catalyzed by EC 2.3.1.118 with acetyl-CoA acting as the acetyl donor, the N-hydroxy metabolites of a number of arylamines being known substrates. The same conjugates can be formed by intramolecular N,O-acetyl transfer, when an arylhydroxamic acid is N-acetylated.95

A very different type of reaction is represented by the conjugation of xenobiotic alcohols with fatty acids, yielding highly lipophilic metabolites accumulating in tissues. Thus, ethanol and haloethanols form esters with, e.g., palmitic acid, oleic acid, linoleic acid, and linolenic acid; enzymes catalyzing such reactions are cholesteryl ester synthase (EC 3.1.1.13) and fatty-acyl-ethyl-ester synthase (EC 3.1.1.67).96 Larger xenobiotics such as tetrahydrocannabinols and codeine are also acylated with fatty acids, possibly by sterol O-acyltransferase (EC 2.3.1.26).

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