THIRAM AND DIMETHYLDITHIOCARBAMIC ACID INTERCONVERSION IN SACCHAROMYCES-CEREVISIAE - A POSSIBLE METABOLIC PATHWAY UNDER THE CONTROL OF THE GLUTATHIONE REDOX CYCLE

A rapid decrease of intracellular glutathione (GSH) was observed when exponentially growing cells of Saccharomyces cerevisiae were treated w ith sublethal concentrations of either dimethyldithiocarbamic acid or thiram [bis(dimethylthiocarbamoyl) disulfide], The underlying mechanis m of this effect possibly involves the intracellular oxidation of dime thyldithiocarbamate anions to thiram, which in turn oxidizes GSH. Over all, a linear relationship was found between thiram concentrations up to 21 mu M and production of oxidized GSH (GSSG), Cytochrome c can ser ve as the final electron acceptor for dimethyldithiocarbamate reoxidat ion, and it was demonstrated in vitro that NADPH handles the final ele ctron transfer from GSSG to the fungicide by glutathione reductase. Th ese cycling reactions induce transient alterations in the intracellula r redox state of several electron carriers and interfere with the resp iration of the yeast, Thiram and dimethyldithiocarbamic acid also inac tivate yeast glutathione reductase when the fungicide is present withi n the cells as the disulfide, Hence, whenever the GSH regeneration rat e falls below its oxidation rate, the GSH:GSSG molar ratio drops from 45 to 1, Inhibition of glutathione reductase may be responsible for th e saturation kinetics observed in rates of thiram elimination and upta ke by the yeast, The data suggest also a leading role for the GSH redo x cycle in the control of thiram and dimethyldithiocarbamic acid fungi toxicity, Possible pathways for the handling of thiram and dimethyldit hiocarbamic acid by yeast are considered with respect to the physiolog ical status, the GSH content, and the activity of glutathione reductas e of the cells.