Aug 3, 1994

Effect of carbamate thioester derivatives of methyl- and 2-chloroethyl isocyanate on glutathione levels and glutathione reductase activity in isolated rat hepatocytes

Biochemical Pharmacology
K KassahunT A Baillie

Abstract

The present study examined the effects of S-(N-methylcarbamoyl)glutathione (SMG), S-(N-methylcarbamoyl)-L-cysteine (L-SMC) and some analogs of these S-linked conjugates of methyl isocyanate (MIC) on the activity of glutathione reductase (GR) in freshly isolated rat hepatocytes and on the levels of reduced and oxidized glutathione (GSH and GSSG) in exposed cells. Both SMG and its monoethyl ester (0.5 mM) were found to inhibit GR weakly, although L-SMC proved to be an effective inhibitor of the enzyme (60 +/- 4% activity remaining after a 4-hr incubation at 0.5 mM). The cysteine adduct (SCC) of 2-chloroethyl isocyanate (CEIC) was a strong inhibitor of GR (27 +/- 1% activity remaining after a 1-hr incubation at 0.1 mM) and was essentially equipotent with the antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU). L-SMC depleted intracellular GSH in a time- and concentration-dependent manner up to 2 hr of incubation, beyond which time GSH levels began to recover. Exposure of cells to the enantiomeric conjugate, D-SMC, led to a similar concentration- and time-dependent inhibition of GR and fall in intracellular GSH, but in this case the depletion of GSH was extensive and was sustained throughout the 5-hr incubation period. Onl...Continue Reading

Mentioned in this Paper

Isocyanates
Antineoplastic Agents
Derivatives
SMITH-MCCORT Dysplasia
Carbamates
Thioester
Glutathione Disulfide
S-(N-methylcarbamoyl)cysteine
Protoplasm
Analog

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