N-Acetyl-cysteine conjugates

Metabolites of hexachlorobutadiene (glutathione conjugate, cysteine conjugate, and its N-acetyl cysteine conjugate) produced effects at lower doses than the parent compound after intraperitoneal injection and there was differential susceptibility between sexes (Ishmael and Lock 1986). A single intraperitoneal dose of 25 mg/kg of the conjugates caused minimal to moderate necrosis in males and severe necrosis in females. On the other hand, a comparable dose caused no effect in males and females after exposure to the parent compound (Ishmael and Lock 1986). 

Table V. Glutathione, cysteine and N—acetyl—cysteine conjugates...

White and coworkers showed that 1 -octyne is metabolized via a different pathway than the one described above. The intermediary metabolites of 1-octyne bind very quickly to proteins and DNA. However, addition of thiol-containing compounds such as N-acetyl-cysteine diminishes this binding in a concentration-dependent manner. Under these conditions the final metabolite is an N-acetyl-cysteine conjugate of 3-oxo-1-octyne, implicating the latter as an intermediary metabolite (Scheme 6). The high reactivity of the 3-0X0 derivative is probably due to its Michael acceptor structure. 

The major forms of iso thiocyanates present in urine are N-acetyl-cysteine conjugates (mercapturic acids) and these have been measured using HPLC with MS detection (Chung et al 1992 Conaway et al 2000 Fowke et al 2003 Petri et al 2003 Rouzaud et al 2004). Appropriate standards can be readily synthesized. Figure 8.9 shows the reaction of an isothiocyanate with 1,2-benzenedithiol which gives rise to a cyclo-condensation product (l,3-benzodithiole-2-thione) and an amine (R-NH2). 

Thiol conjugation Epoxides Glutathione S-transferases (glutathione or N-acetylcysteine) Glutathione or N-acetyl cysteine thioethers... 

Radiolabeled benzene (=340 mg/kg) was administered by oral intubation to rabbits 43% of the label was recovered as exhaled unmetabolized benzene and 1.5% was recovered as carbon dioxide (Parke and Williams 1953). Urinary excretion accounted for about 33% of the dose. The isolated urinary metabolites were mainly in the form of conjugated phenols. Phenol was the major metabolite accounting for about 23% of the dose or about 70% of the benzene metabolized and excreted in the urine. The other phenols excreted (percentage of dose) were hydroquinone (4.8%), catechol (2.2%), and trihydroxybenzene (0.3%). L-phenyl-N-acetyl cysteine accounted for 0.5% of the dose. Muconic acid accounted for 1.3% the rest of the radioactivity (5-10%) remained in the tissues or was excreted in the feces (Parke and Williams 1953). 

Except in the case of N-acetyl-cysteine, the chemical problems encountered In synthesis of the conjugates summarized under this heading are similar due to the amphoteric character of the nucleophiles. In general Che reactions with thiol compounds must be carried out In an inert atmosphere in order to minimize oxidation. The starting material, for synthesis of some of Che xenobiotic conjugates below, require multistep syntheses, but the procedures for their preparations will not be discussed here. 

Table VI. Aryl glutathione, cysteine and N-acetyl-cystelne conjugates synthesized by nucleophilic displacement of halogen or some other leaving group Including the one obtained by dlazotlsatlon of arylamlnes.

In a similar reaction, chlorinated thiophenols were added to a-acetamldoacryllc acid for the synthesis of mercapturlc acids of polychlorinated benzenes (196). This method produces a DL-mlxture of the N-acetyl-cystelne conjugate and It Is limited to the synthesis of mercapturlc acids and cysteine conjugates, the latter obtained after deacetylation. 

Glutathione is involved in the conjugation of certain toxic hydrocarbons by the liver. These are eventually excreted as mercapturic acids, S-substituted N-acetyl-cysteines. Such compounds have been isolated from the urine of many animals including man. 

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). 

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... 

Van Bladeren PJ, Breimer DD, Van Fluijgevoort JA, et al. 1981. The metabolic formation of N-acetyl-S-2-hydroxyethyl-L-cysteine from tetradeutero-1,2-dibromoethane. Relative importance of oxidation and glutathione conjugation in vivo. Biochem Pharmacol 30 2499-2502. 

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