The genetic mechanisms underlying
cisplatin (DDP) resistance in yeast were investigated by examining the cytotoxicity of DDP to Schizosaccharomyces pombe mutants that were either hypersensitive or resistant to Cd. Despite reports that have linked
glutathione (GSH) to DDP resistance in human
cancer cells, we found that a mutant of S. pombe that was hypersensitive to Cd by virtue of a 15-fold reduction in GSH level and lack of
phytochelatin production was as tolerant as the wild-type strain to DDP. A mutant that harbored a mutation in hmt1, the gene encoding an
ATP-binding cassette-type transporter for vacuolar sequestration of a
phytochelatin/Cd complex, exhibited only mild
hypersensitivity to DDP even though it was 100-fold more sensitive to Cd. Overexpression of hmt1 in wild-type or mutant cells conferred tolerance to Cd but failed to do the same for DDP. However, a strain that produced 6-fold more
sulfide than wild-type cells was found to be 6-fold more resistant to DDP and twice as resistant to Cd; an association between DDP resistance and
sulfide production was observed in three other strains that were examined, and overproduction of
sulfide was accompanied by reduced platination of
DNA. These results indicate that GSH and the GSH-derived
phytochelatin peptides do not play critical roles in determining sensitivity to DDP in S. pombe but rather identify increased production of
sulfide as a possible new mechanism of DDP resistance that may also be relevant to human cells.