Brain uptake of S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine, the glutathione and cysteine S-conjugates of the neurotoxin dichloroacetylene.
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, 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.
Patel
N J
NJ
Department of Pharmacology, University of Rochester, School of Medicine and Dentistry, NY 14642.
Fullone
J S
JS
Anders
M W
MW
D000114:Acetylene / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D001711:Biotransformation; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005978:Glutathione / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009498:Neurotoxins / Q000493:pharmacokinetics*; D051381:Rats
D009498:Neurotoxins; C039961:S-(1,2-dichlorovinyl)cysteine; C002978:dichloroacetylene; C041464:S-(1,2-dichlorovinyl)glutathione; D005978:Glutathione; D003545:Cysteine; D000114:Acetylene