Glutathione-dependent biosynthesis and bioactivation of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine, the glutathione and cysteine S-conjugates of dichloroacetylene, in rat tissues and subcellular fractions.
Dichloroacetylene is neurotoxic, nephrotoxic, and nephrocarcinogenic. The present experiments were designed to test further the hypothesis that the glutathione conjugate of dichloroacetylene, S-(1,2-dichlorovinyl)glutathione (DCVG), may be involved in dichloroacetylene-induced neurotoxicity. Hence, the biosynthesis of DCVG from dichloroacetylene and glutathione was studied in cytosolic, microsomal, and mitochondrial fractions of liver, lung, brain, and kidney. Enzymatic formation of DCVG was observed in liver microsomes and mitochondria, but only nonenzymatic formation of DCVG was seen in lung, brain, and kidney. The KM and Vmax for DCVG biosynthesis with glutathione as the variable substrate were 0.40 +/- 0.28 mM and 487 +/- 90.3 nmol/mg protein/min, respectively. No region-specific differences in the rates of DCVG biosynthesis in the brain were observed. In whole brain homogenates, DCVG was hydrolyzed to DCVC, which was biotransformed to pyruvate and S-(1,2-dichlorovinyl)-3- mercaptopyruvate, indicating cysteine conjugate beta-lyase-catalyzed beta-elimination and transamination reactions in cerebellar tissues. These findings indicate that the glutathione-dependent bioactivation of dichloroacetylene may be involved in the dichloroacetylene-induced neurotoxicity.
Patel
N
N
Department of Pharmacology, University of Rochester, NY 14642.
Birner
G
G
Dekant
W
W
Anders
M W
MW
D000114:Acetylene / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D013437:Carbon-Sulfur Lyases; D003545:Cysteine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005978:Glutathione / Q000031:analogs & derivatives* / Q000096:biosynthesis; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
C039961:S-(1,2-dichlorovinyl)cysteine; C002978:dichloroacetylene; C041464:S-(1,2-dichlorovinyl)glutathione; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase; D005978:Glutathione; D003545:Cysteine; D000114:Acetylene