Acetylation conjugation reactions

Acetylation is another conjugation reaction, but it differs from the foregoing examples in that the products tend to be less polar than the substrates. 

The metabolic formation of N-sulfonyloxy-N-acetyl-2-aminofluorene (N-sulfonyloxy-AAF) and its observed electrophilic reactivity, provided the first evidence for the importance of enzymatic conjugation reactions in chemical carcinogenesis (23,24). This reaction was shown to be catalyzed by PAPS-dependent sulfotrans-ferases that are located predominantly in liver cytosol and has been subsequently demonstrated for N-hydroxy arylamide metabolites of several other carcinogens, including N-acetyl-4-aminobiphenyl (AABP), benzidine, N-acetyl-2-aminophenanthrene and phenacetin. 

Cascade Blue acetyl azide is soluble in aqueous solution, but the reactive azide group will hydrolyze and should be used immediately in a conjugation reaction. A concentrated stock solution may be prepared in water, dissolved quickly, and an aliquot quickly added to a buffered reaction medium. For aqueous reactions, a pH range of 7-9 is optimal. Avoid amine-containing buffers. 

The principal mercapturic acid derivative, N-acetyl-S-(2-hydroxyethyl-)L-cysteine, and other related metabolites are derived from the conjugation reaction of 1,2-dibromoethane with glutathione, a molecule present in mammalian cells. This suggests that the primary pathway of... 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

A 2-Methylpyridine can be deprotonated by a base such as sodium methoxide and the resultant anion can be reacted with ben-zaldehyde to form a hydroxylated adduct (Scheme 2.21). This product can then be dehydrated by acid, or base, to form the conjugated compound stilbazole. Alternatively 2-methylpyridine can be A -acetylated by reaction with acetic anhydride and the initial product deprotonated to give an A -acetylenamine intermediate that traps benzaldehyde, A similar reaction to that of the first procedure occurs, but under the reaction conditions the zwitterionic (dipolar) product eventually loses acetic acid, perhaps by an interna shift of an acetyl group from nitrogen to oxygen. 

Type I reactions include the formation of glycosylated, sulfated, methylated, and acetylated conjugates, whereas type II reactions include peptide and glutathione conjugation. 

Figure 13.10. NAT-mediated metabolic activation of heterocyclic aromatic amines. 2-AF is not a NAT substrate for A-aectylation (compare with 2-NA, 4-ABP A-acetylation in Figure 13.9). 2-AF is detoxified by P4502B1 ring hydroxylation. 2-AF is also metabolized via P4501A2-mediated A-hydroxylation. The resultant A-hydroxy 2-AF is a good substrate of conjugation reactions by NATs as well as by UGTs and SULTs and is converted to reactive metabolites for DNA adduct formation.

Conjugation reactions of xenobiotics or their metabolites with endogenous substrates produce highly hydrophilic metabolites however, to a lesser extent functional groups may be also methylated or acetylated to produce less hydrophilic compounds. 

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