Sulfhydryl compounds inhibit the cyto- and geno-toxicity of o-phenylphenol metabolites in CHO-K1 cells.
The effects of cysteine and reduced glutathione (GSH) on the genotoxicity of o-phenylphenol (OPP) and its metabolites, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), were examined using the frequency of sister-chromatid exchanges (SCEs) and chromosome aberrations in CHO-K1 cells as parameters. Cytotoxic (cell-progression delay) and cytogenetic effects induced by a 3-h treatment with OPP, PHQ (100 micrograms/ml) or PBQ (50 micrograms/ml) with S9 mix after a 27-h expression time were inhibited by cysteine or GSH (3-10 mM). Materials corresponding to the cysteine or GSH adducts were found by HPLC in each incubation mixture. In the culture without S9 mix, PHQ and PBQ showed severe cytotoxicity since no metaphases could be obtained at doses over 25 and 5 micrograms/ml, respectively, and the sulfhydryl compounds inhibited the toxicity by the formation of adducts with PBQ and by inhibiting the formation of PBQ in the case of PHQ. With PHQ, the sulfhydryl compounds appeared to inhibit autooxidation. However, the sulfhydryl compounds did not inhibit the cytotoxic and cytogenetic effects caused by OPP in the cell mixture without S9 mix, but on the contrary intensified them. No adduct formation was detected in the incubation solution. On the basis of these results, it is considered that electrophilic quinone (PBQ) and/or semiquinone (phenylsemiquinone, PSQ) radicals, capable of binding to nucleophilic small molecules (such as cysteine and GSH) or (biological) macromolecules, are produced from metabolite PHQ in metabolic oxidation of OPP, and induce cyto- and geno-toxic effects in the cells. The cyto- and geno-toxic effects of OPP itself to the cells are clearly independent of any electrophilic radical reaction.
Tayama
S
S
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
Nakagawa
Y
Y
D000818:Animals; D016227:Benzoquinones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002869:Chromosome Aberrations; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D006873:Hydroquinones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012854:Sister Chromatid Exchange; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*
D016227:Benzoquinones; D001713:Biphenyl Compounds; D006873:Hydroquinones; D013438:Sulfhydryl Compounds; C029322:phenylbenzoquinone; C004369:2-phenylphenol; D005978:Glutathione; C066330:phenylhydroquinone; D003545:Cysteine