Brain uptake of S-(1,2-dichlorovinyl)glutathione and [formula omitted], the glutathione and cysteine S-conjugates of the neurotoxin dichloroacetylene

Abstract

Dichloroacetylene causes trigeminal neuropathy in humans and animals. Glutathione conjugation of dichloroacetylene affords S-(1,2-dichlorovinyl)glutathione (DCVG), which is hydrolyzed to S-(1,2- dichlorovinyl)- l-cysteine (DCVC). This study was undertaken to test the hypothesis that the neurotoxicity of dichloroacetylene may be associated with glutathione S-conjugate formation and brain uptake and bioactivation of the dichloroacetylene-derived S-conjugates. With the Oldendorf technique 28, the Brain Uptake Index for [ 35S]DCVC and [ 35S]DCVG was determined and compared with the uptake of [ 35S]methionine and [ 14C]sucrose. Brain uptake of DCVC exceeded uptake of methionine and DCVG uptake was comparable to methionine uptake. Both [ 35S]DCVC and [ 35S]DCVG were recovered intact in brain tissue. The uptake of the 35S-labeled S-conjugates was inhibited by unlabeled DCVC and DCVG in a concentration-dependent manner. The data indicated that DCVC, but not DCVG, was transported by the sodium-independent system-L transporter for neutral amino acids. In vitro studies revealed that DCVG can be hydrolyzed to DCVC by brain tissue in a concentration-dependent manner.