Quinol-glutathione conjugate-induced mutation spectra in the supF gene replicated in human AD293 cells and bacterial MBL50 cells

Jeongmi K. Jeong, Gerald N. Wogan, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3641-3645
Number of pages5
JournalCancer Research
Volume59
Issue number15
StatePublished - Aug 1 1999
Externally publishedYes

Fingerprint

Hydroquinones
Glutathione
Mutation
Genes
Single-Stranded DNA Breaks
Genetic Vectors
Gastrin-Secreting Cells
Mutation Rate
Reactive Oxygen Species
Plasmids
Escherichia coli
hydroquinone

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Quinol-glutathione conjugate-induced mutation spectra in the supF gene replicated in human AD293 cells and bacterial MBL50 cells. / Jeong, Jeongmi K.; Wogan, Gerald N.; Lau, Serrine; Monks, Terrence.

In: Cancer Research, Vol. 59, No. 15, 01.08.1999, p. 3641-3645.

Research output: Contribution to journalArticle

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abstract = "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.",
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