Metabolic conjugative reactions

Table V. Some "Species Defects" in Metabolic Conjugation Reactions Reaction Affected species (reference)...

Formation of sulfate esters is one of the metabolic conjugation reactions (Phase II reactions, see Chapter 34). Sulfates of estradiol," s giucose," menadiol," and... 

Formation of sulfate esters is one of the metabolic conjugation reactions (phase II reactions, see Chapter 31). Sulfates of estradiol, glucose, menadiol, and hydro-xyethyl-theophylline have been prepared (Fig. 36.9). As a rule sulfuric acid esters, compared with their phosphoric analogues, are resistant to enzymatic hydrolysis in and their conversion to the parent drug is questionable. 

TABLE 6.9 Metabolic Conjugative Reactions That Lead to Conjugates... 

CONJUGATION REACTIONS PREPARE XENOBIOTICS FOR EXCRETION IN PHASE 2 OF THEIR METABOLISM... 

Testa B (2006) Principles of drug metabolism 2 hydrolysis and conjugation reactions. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.06... 

In BA metabolism, the procarcinogenic BA trans-3.4-dihydrodiol (26) constitutes 1.5-4% of all the metabolites formed by rat liver microsomes (27) and a major component of the free dihydrodiols formed by mouse skin maintained in short-term organ culture (28). In this system (28). the noncarcinogenic dihydrodiols may be preferentially removed by conjugation reactions to yield water soluble products. 

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. 

Acetyltransferases catalyze the acetylation of amino, hydroxyl, and thiol functional groups. Acetylation of hydroxy and thiol groups is comparatively rare and of much less importance in alkaloid metabolism than reactions with amino functional groups. The types of amines that are acetylated include arylamines (the major route of metabolism in many species), aliphatic amines, hydrazines, sulfonamides, and the a-amino group of cysteine conjugates. The purification, physical properties, and specificity of the N-acetyltransfereases have been reviewed (116-118). 

While some conjugation reactions fail to totally meet the above criteria, they all satisfy at least one criterion. But what about the reactions of hydrolysis On the one hand, these fulfil none of the three above criteria, with the partial exception that the molecule (water) that reacts with the substrate is a polar one. On the other hand, the metabolic reactions of hydrolysis modify pre-existing functional groups of the substrates and, thus, meet the definition of functionalization reactions. 

Conjugation Reactions in Drug Metabolism , Ed. G. J. Mulder, Taylor Francis, London, 1990. 

B. Ketterer, The Role of Nonenzymatic Reactions of Glutathione in Xenobiotic Metabolism , Drug Metab. Rev. 1982, 13, 161 - 187 B. Ketterer, G. J. Mulder, Glutathione Conjugation , in Conjugations Reactions in Drug Metabolism , Ed. G. J. Mulder, Taylor and Francis, London, 1990, p. 307 - 364. 

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