Mutagenicity of the mycotoxin patulin in cultured Chinese hamster V79 cells, and its modulation by intracellular glutathione.
Because the ability of the mycotoxin patulin (PAT) to cause gene mutations in mammalian cells is still ambiguous, we have studied the mutagenicity of PAT at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene locus in cultured Chinese hamster V79 cells with normal, depleted, and elevated glutathione (GSH) levels. PAT was more toxic to GSH-depleted cells than to normal cells and caused an increase of the intracellular GSH level in normal and GSH-depleted cells. It also caused synchronization of the cell cycle due to a temporary accumulation of cells in the G2/M phase; this G2/M arrest was more persistent in GSH-depleted than in normal cells. PAT gave rise to a clear and concentration-dependent induction of HPRT mutations at non-cytotoxic concentrations in V79 cells with normal GSH level; the lowest PAT concentration causing a significant number of mutant cells was 0.3 micromolar, and the mutagenic potency of PAT equaled that of the established mutagen 4-nitroquinoline-N-oxide. The mutagenicity of PAT was again more pronounced, by a factor of about three, in GSH-depleted V79 cells. Elevated GSH levels abolished all observed effects of PAT. These data support the notion that PAT is a mutagenic mycotoxin, in particular in cells with low GSH concentration. The ability of PAT to cause gene mutations in mammalian cells might have a bearing on its carcinogenicity.
Schumacher
David M
DM
Institute of Food Chemistry and Toxicology, University of Karlsruhe, P.O. Box 6980, 76128 Karlsruhe, Germany.
Metzler
Manfred
M
Lehmann
Leane
L
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D010365:Patulin / Q000633:toxicity*
D009153:Mutagens; D019328:Buthionine Sulfoximine; D010365:Patulin; D007041:Hypoxanthine Phosphoribosyltransferase; D005978:Glutathione