Conjugates, cysteine

Another type of detoxication involves the production of cysteine conjugates, which are readily excreted. (Again, organomercury compounds show their affinity for -SH groups). Methyl mercuric cysteine is an important biliary metabolite in the rat and is degraded within the gut (presumably by microorganisms) to release inorganic mercury (see IAEA Report 137, 1972). 

Dekant W, Vamvakas S, Berthold K, et al. 1986c. Bacterial P-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene, and hexachlorobutadiene. Chem Biol Interact 60 31-45. 

Cysteine conjugation Mercapturic acid (from GSH conjugation) r-ch=ch2> R-CH2-CH2-Cys +121 (119) +161... 

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). 

Cysteine conjugates can also be degraded by the enzyme cysteine conjugate 0-lyase, which involves pyridoxal as a cofactor as shown in Figure 7.19 (26). 

FIGURE 7.19 Metabolism of a cysteine conjugate mediated by cysteine conjugate 0-lyase. 

Isolated proximal tubules have been utilized to study the mechanisms of nephrotoxicity induced by antibiotics (Sina et al., 1985, 1986), radiocontrast dyes (Humes et al., 1987), metals (Rylander et al., 1985), anoxia (Weinberg, 1985 Weinberg et al., 1987), cellular oxidants (Messana et al., 1988), cysteine conjugates (Rylander et al., 1985 Schnellman et al., 1987 Zhang and Stevens, 1989), and a variety of nephrotoxic bromobenzene metabolites (Schnellman and Mandel, 1986 Schnellman et al., 1987). 

Zhou L, Erickson RR, Hardwick JP, Park SS, Wrighton SA, et al. 1997a. Catalysis of the cysteine conjugation and protein binding of acetaminophen by microsomes from a human lymphoblast line transfected with the cDNAs of various forms of human cytochrome P450. J Pharmacol Exp Ther 281 785-790. 

CYSTATHIONINE /3-LYASE CYSTATHIONINE /3-SYNTHASE CYSTEINE CONJUGATE /3-LYASE CYSTEINE LYASE... 

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). 

Cysteine conjugates of hexachlorobutadiene are converted to thio derivatives (e.g.,... 

Green T, Odum J. 1985. Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes. Chem Biol Interactions 54 15-31. 

Jaffe DR, Hassall CD, Brendel K. 1983. In wVoand in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J Toxicol Environ Health 11 857-867. 

Jones TW, Chen Q, Schaeffer V, et al. 1988. Immunohistochemical localization of glutamine transaminase K, a rat kidney cysteine conjugate p-lyase, and the relationship to the segment specificity of cysteine conjugate nephrotoxicity. Mai Pharm 34 621-627. 

MacFarlane M, Foster JR, Gibson GG, et al. 1989. Cysteine conjugate [3-lyase of rat kidney cytosol Characterization, immunocytochemical localization, and correlation with hexachlorobutadiene nephrotoxicity. Toxicol AppI Pharmacol 98 185-197. 

The cysteine conjugates appeared to be key metabolil es, occupying pivotal positions in the pathway. S-(Pentachloro-phenyl)cysteine was not demonstrated in vitro, but it was a minor metabolite in peanut plants. This anomoly appeared to be due to the kinetics of the various reactions. A cysteine conjugate was clearly shown to be a key intermediary metabolite in the metabolism of the GSH conjugate of atrazine in sorghum (Figure 1). 

Pentachlorothiophenol was formed Iji vitro from S-(PCP)Cys by a C-S lyase enzyme from onion root. This enzyme was active with S-(PCP)Cys, S-(2,M-dinitrophenyl)cysteine, and the cysteine conjugate of propachlor. A C-S lyase from Alblzzla lophanta was previously shown to utilize a broad range of cysteine derivatives (2U). 

Evidence was also provided that Insoluble residues may be produced from GSH conjugates via cysteine conjugate or thiol Intermediates. These studies also suggested that certain reactions should be studied in greater detail to assess their importance in pesticide metabolism l.e., the C-S lyase reaction, the methyl transferase reaction, and the transamination reaction. 

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