Mercapturic acid acetylation

Commandeur JNM, Vermeulen NPE. 1990a. Identification of N-acetyl-S-(2,2-dichlorovinyl) and N-acetyl-S-(l,2-dichlorovinyl)-L-cysteine as two regioisomeric mercapturic acids of trichloroethylene in the rat. Chem Res Toxicol 3 212-218. 

Co., Richmond, Calif. Hexamethyleneimine (HMI) was purchased from Matheson Coleman Bell Co. S (Hexahydro-[2-I tC]azepine-l-car-bonyl)-N-acetyl-L-cysteine (molinate mercapturic acid) was provided by DeBaun et al. (12). Caprolactam was purchased from J.T,... 

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... 

Following oral administration of 50 mg/kg bw 2,3-dibromopropan-l-ol to male Sprague-Dawley rats, two urinary mercapturic acid metabolites were identified as N-acetyl-5 -(2,3-dihydroxypropyl)cysteine and A, W-bis-acetyl-N<5"-(l,3-bis-cysteinyl)-propan-2-ol, respectively. It was inferred that 3-bromo-l,2-propane epoxide is an intermediate in the metabolism of 2,3-dibromopropan-l-ol. In addition, (3-bromolactate was produced, presumably as a result of hydrolysis to the a-bromohydrin and subsequent oxidation (Jones Fakhouri, 1979). Marsden and Casida (1982) identified small amounts of 2-bromoacrylic acid in the urine of rats injected intraperitoneally with 2,3-dibromopropan-l-ol and suggested that this arose by oxidation and dehydrobromi-nation, with 2-bromoacrolein as an unstable intermediate. 

The dog does, however, acetylate the Nl, sulfonamido group of sulfanilamide (chap. 4, Fig. 68), and also acetylates aliphatic amino groups. The guinea pig is unable to acetylate aliphatic amino groups such as that in cysteine. Consequently, it excretes cysteine rather than N-acetylcysteine conjugates or mercapturic acids. Birds, some amphibia, and insects are also able to acetylate aromatic amines, but reptiles do not use this reaction. 

Urinary metabolites of acrylonitrile include 5 -(2-cyanoethyl)mercapturic acid, N-acet T-3-carboxy-5-cyanotctrahydro-I,4-3//-thiazine and thiocyanate (Kopecky et al., 1979 Langvardt et al., 1980 Gut c/ al., 1981 Sapota, 1982). The proportion excreted as thiocyanate by rats is far higher (23% of dose) after oral dosing than after intraperitoneal, intravenous or subcutaneous administration (1-4% of dose Gut et al., 1981). Other metabolites derived from the mercapturic acid pathway include. S -carboxymethylcys-teine,. S -hydroxyethylmercapturic acid [jV-acetyl-5 -(2-hydroxyethyl)cysteine] and thiodi-glycolic acid (Muller et al., 1987). 

FIGURE 15-3 Acetaminophen metabolism. In the liver, acetaminophen is metabolized to a toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is quickly detoxified by conjugation with glutathione (GSH), forming mercapturic acid, which is eliminated via the urine. High doses of acetaminophen or liver dysfunction can result in accumulation of NAPQI and subsequent toxicity to liver proteins. 

Figure 7.10 Glutathione conjugate of a xenobiotic species (HX-R), followed by formation of glutathione and cysteine conjugate intermediates (both of which may be excreted in bile) and acetylation to form readily excreted mercapturic acid conjugate.

Acetylation reactions catalyzed by acetyltransferase enzymes involve the attachment of the acetyl moiety, shown as the final step in glutathione conjugation and the production of a mercapturic acid conjugate in Figure 7.10. The cofactor upon which the acetyltransferase enzyme acts in acetylation is acetyl coenzyme A ... 

L-Cysteine, N-acetyl-S-(3,4-dihydroxybutyl) mercapturic acid conjugate... 

This activity has been demonstrated in mammalian liver and kidney, as well as in intestinal bacteria. Glutathione S-transle rases catalyze the formation of glutathione conjugates, which are processed via the mercapturic biosynthetic pathway, to acety-lated cysteine -conjugates. The unacetylated premercapturic acids are substrates for cysteine 5-conjugate P-lyase, whereas the acetylated cysteine -conjugates, the mercapturic acids, do not function as substrates for the enzymes. 

SYNS l-a-ACETAMIDO-P-MERCAPTOPROPIONIC ACID ACETEIN ACETYLCYSTEINE N-ACETYLCYSTEINE N-ACETYL-N-CYSTEINE N-ACETYL-l-CYSTEINE (9CI) N-ACETYL-3-MERCAPTO-AL.ANINE AIRBRON BRONCHOL-YSIN FLUIMUCETIN FLULMUCIL FLUMICIL INSPIR MERCAPTURIC ACID (R)-MERCAP-TURIC ACID MUCOLYTICUM MUCOLYTICUM LAPPE MUCOMYST MUCOSOLVIN NAC NAC-TB NSC-111180 PARVOLEX RESPAIRE... 

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