Quinol-glutathione conjugate-induced mutation spectra in the supF gene replicated in human AD293 cells and bacterial MBL50 cells.
Hydroquinone is a nephrocarcinogen in rats but generally tests negative in standard mutagenicity assays. However, 2,3,5-tris-(glutathion-S-yl)hydroquinone, a potent nephrotoxic metabolite of hydroquinone, and 2-bromo-bis-(glutathion-S-yl)hydroquinone, another cytotoxic quinol-glutathione (GSH) conjugate, cause extensive single strand breaks in DNA in a manner that is dependent on the formation of reactive oxygen species. We, therefore, investigated whether quinol-GSH conjugates have the potential to behave as genotoxicants. The shuttle vector pSP189, containing the supF gene, was treated with 2,3,5-tris-(glutathion-S-yl)hydroquinone and replicated in both human AD293 cells and Escherichia coli MBL50 cells. The mutation frequency increased 4.6- and 2.6-fold in human AD293 and bacterial MBL50 cells, respectively. Base substitutions were the major type of mutations, and they occurred predominantly at G:C sites in both cell types. A high frequency of deletions (30%), including < 10- and > 10-bp deletions, were observed in AD293-replicated plasmids. The most common types of mutations in AD293 cells were G:C to A:T transitions (33.8%) and G:C to T:A (29.4%) and G:C to C:G (19.1%) transversions. In MBL50 cells, the major mutations were G:C to T:A (33.8%) and G:C to C:G (31.3%) transversions and G:C to A:T transitions (27.5%). The mutation spectra were similar to those reported for *OH-induced mutations, suggesting that *OH generated from polyphenolic-GSH conjugates not only plays a role in cytotoxicity but also provides a basis for their mutagenicity and carcinogenicity.
Jeong
J K
JK
Massachusetts Institute of Technology, Division of Toxicology, Cambridge 02139, USA. scouser@mail.utexas.edu
Wogan
G N
GN
Lau
S S
SS
Monks
T J
TJ
D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004269:DNA, Bacterial / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005419:Flavonoids; D016153:Genes, Suppressor; D005978:Glutathione / Q000031:analogs & derivatives* / Q000502:physiology / Q000633:toxicity; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D007668:Kidney; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity*; D010636:Phenols / Q000009:adverse effects* / Q000493:pharmacokinetics; D017354:Point Mutation; D011108:Polymers / Q000009:adverse effects* / Q000493:pharmacokinetics; D059808:Polyphenols; D012343:RNA, Transfer / Q000235:genetics*; D017382:Reactive Oxygen Species
D004269:DNA, Bacterial; D005419:Flavonoids; D006873:Hydroquinones; D009153:Mutagens; D010636:Phenols; D011108:Polymers; D059808:Polyphenols; D017382:Reactive Oxygen Species; C096275:supF tRNA; C078765:2,3,5-(triglutathion-S-yl)hydroquinone; D004247:DNA; D012343:RNA, Transfer; D005978:Glutathione