Quinone thioether-mediated DNA damage, growth arrest, and gadd153 expression in renal proximal tubular epithelial cells

Jeongmi K. Jeong, James L. Stevens, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

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Abstract

Although the conjugation of quinones with glutathione is associated with the process of detoxication, the reaction frequently facilitates quinone-induced toxicity. Thiol conjugates of quinones retain the ability to redox cycle and generate reactive oxygen species (RES), contributing to the biological (re)activity of a variety of polyphenelic compounds. 2-Bromo- bis(glutathion-S-yl)hydroquinone (2-Br-bis(GSyl)HQ) and 2-bromo-6- (glutathion-S-yl)hydroquinone [2-Br-6-(GSyl)HQ] are potent nephrotoxicants in rats, inducing rapid karyolysis in vivo and DNA single-strand breaks in cultured renal proximal tubular epithelial cells (LLC-PK1). We investigated the cellular and molecular responses initiated after exposure of LLC-PK1 cells to 2-Br-bis(GSyl)HQ and 2-Br-6-(GSyl)HQ. Both quinone thioethers cause the concentration-dependent formation of DNA single-strand breaks, rapidly (2-10 min) inhibit DNA synthesis, and increase the expression of gadd153, a gene responsive to growth arrest and DNA damage. The addition of catalase to LLC-PK1 cells exposed to 2-Br-6-(GSyl)HQ or 2-Br-bis(GSyl)HQ effectively prevents gadd153 induction, which is consistent with findings that the gadd153 gene is subject to redox modulation and that ROS play an important role in quinone thioether-mediated cytotoxicity. Deferexamine pretreatment also diminishes gadd153 induction, suggesting that in renal proximal tubular epithelial cells, decreased expression of gadd153 is not dependent on the removal of hydrogen peroxide per se but rather on preventing the generation of hydroxyl radical. Chelation of intracellular calcium with ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester also reduces gadd153 induction by 2-Br-6-(GSyl)HQ and 2-Br- bis(GSyl)HQ, suggesting a role for calcium in the signaling process. Thus, 2-Br-6-(GSyl)HQ and 2-Br-bis(GSyl)HQ activate a genomic stress response via a signaling pathway that may include ROS, Ca2+, and DNA damage.

Original languageEnglish (US)
Pages (from-to)592-598
Number of pages7
JournalMolecular Pharmacology
Volume50
Issue number3
StatePublished - Sep 1996
Externally publishedYes

Fingerprint

Sulfides
DNA Damage
Epithelial Cells
Kidney
Growth
LLC-PK1 Cells
Single-Stranded DNA Breaks
Quinones
Oxidation-Reduction
Glutathione
Calcium Signaling
Ethylene Glycol
Sulfhydryl Compounds
Hydroxyl Radical
Ether
Catalase
Hydrogen Peroxide
Genes
2-bromo-6-(glutathion-S-yl)hydroquinone
benzoquinone

ASJC Scopus subject areas

  • Pharmacology

Cite this

Quinone thioether-mediated DNA damage, growth arrest, and gadd153 expression in renal proximal tubular epithelial cells. / Jeong, Jeongmi K.; Stevens, James L.; Lau, Serrine; Monks, Terrence.

In: Molecular Pharmacology, Vol. 50, No. 3, 09.1996, p. 592-598.

Research output: Contribution to journalArticle

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AB - Although the conjugation of quinones with glutathione is associated with the process of detoxication, the reaction frequently facilitates quinone-induced toxicity. Thiol conjugates of quinones retain the ability to redox cycle and generate reactive oxygen species (RES), contributing to the biological (re)activity of a variety of polyphenelic compounds. 2-Bromo- bis(glutathion-S-yl)hydroquinone (2-Br-bis(GSyl)HQ) and 2-bromo-6- (glutathion-S-yl)hydroquinone [2-Br-6-(GSyl)HQ] are potent nephrotoxicants in rats, inducing rapid karyolysis in vivo and DNA single-strand breaks in cultured renal proximal tubular epithelial cells (LLC-PK1). We investigated the cellular and molecular responses initiated after exposure of LLC-PK1 cells to 2-Br-bis(GSyl)HQ and 2-Br-6-(GSyl)HQ. Both quinone thioethers cause the concentration-dependent formation of DNA single-strand breaks, rapidly (2-10 min) inhibit DNA synthesis, and increase the expression of gadd153, a gene responsive to growth arrest and DNA damage. The addition of catalase to LLC-PK1 cells exposed to 2-Br-6-(GSyl)HQ or 2-Br-bis(GSyl)HQ effectively prevents gadd153 induction, which is consistent with findings that the gadd153 gene is subject to redox modulation and that ROS play an important role in quinone thioether-mediated cytotoxicity. Deferexamine pretreatment also diminishes gadd153 induction, suggesting that in renal proximal tubular epithelial cells, decreased expression of gadd153 is not dependent on the removal of hydrogen peroxide per se but rather on preventing the generation of hydroxyl radical. Chelation of intracellular calcium with ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester also reduces gadd153 induction by 2-Br-6-(GSyl)HQ and 2-Br- bis(GSyl)HQ, suggesting a role for calcium in the signaling process. Thus, 2-Br-6-(GSyl)HQ and 2-Br-bis(GSyl)HQ activate a genomic stress response via a signaling pathway that may include ROS, Ca2+, and DNA damage.

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