Glutathione depletion enhances the formation of endogenous cyclic DNA adducts derived from t-4-hydroxy-2-nonenal in rat liver

Fung Lung Chung, Despina Komninou, Lei Zhang, Raghu Nath, Jishen Pan, Shantu Amin, John Richie

Research output: Contribution to journalArticle

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Abstract

Earlier, we detected the cyclic adducts of deoxyguanosine (dG) derived from t-4-hydroxy-2-nonenal (HNE), a long chain α,β-unsaturated aldehyde (enal) product from oxidation of ω-6 polyunsaturated fatty acids, in tissue DNA of rats and humans as endogenous DNA damage. Recent evidence implicates the cyclic HNE adducts in human liver carcinogenesis. Because glutathione (GSH) protects against oxidative stress, we undertook a study to examine the effect of GSH depletion on the HNE-derived cyclic adducts in vivo. Four F344 rats were administered L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH biosynthesis, at 10 mM in drinking water for 2 weeks. Rats in the control group were given water only. Livers were harvested, and each liver was divided into portions for GSH and DNA adduct analyses. The BSO treatment depleted hepatic GSH by 77%; the GSH levels were reduced from 6.3 ± 0.3 in the control rats to 1.5 ± 0.1. μmol/g tissues in the treated group. The formation of HNE-dG adducts, analyzed by an HPLC-based 32P- postlabeling assay, was increased by 4-fold, from 6.2 ± 2.2 nmol/mol dG in liver DNA of control rats to 28.5 ± 16.1 nmol/mol dG in the rats treated with BSO (p < 0.05). The formation of 8-oxodG in liver DNA was also increased as a result of BSO treatment, although the increase was not statistically significant. These results further support the endogenous origin of HNE-dG adducts and, more importantly, indicate a critical role that GSH plays in protecting against in vivo formation of the promutagenic cyclic DNA adducts derived from HNE.

Original languageEnglish (US)
Pages (from-to)24-27
Number of pages4
JournalChemical Research in Toxicology
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2005

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Deoxyguanosine
DNA Adducts
Liver
Glutathione
Rats
Rat control
DNA
Tissue
Oxidative stress
Biosynthesis
Unsaturated Fatty Acids
Aldehydes
Drinking Water
Inbred F344 Rats
Assays
DNA Damage
4-hydroxy-2-nonenal
2-nonenal
Carcinogenesis
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{20cb631d41f047d19c03ff9edfcc254f,
title = "Glutathione depletion enhances the formation of endogenous cyclic DNA adducts derived from t-4-hydroxy-2-nonenal in rat liver",
abstract = "Earlier, we detected the cyclic adducts of deoxyguanosine (dG) derived from t-4-hydroxy-2-nonenal (HNE), a long chain α,β-unsaturated aldehyde (enal) product from oxidation of ω-6 polyunsaturated fatty acids, in tissue DNA of rats and humans as endogenous DNA damage. Recent evidence implicates the cyclic HNE adducts in human liver carcinogenesis. Because glutathione (GSH) protects against oxidative stress, we undertook a study to examine the effect of GSH depletion on the HNE-derived cyclic adducts in vivo. Four F344 rats were administered L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH biosynthesis, at 10 mM in drinking water for 2 weeks. Rats in the control group were given water only. Livers were harvested, and each liver was divided into portions for GSH and DNA adduct analyses. The BSO treatment depleted hepatic GSH by 77{\%}; the GSH levels were reduced from 6.3 ± 0.3 in the control rats to 1.5 ± 0.1. μmol/g tissues in the treated group. The formation of HNE-dG adducts, analyzed by an HPLC-based 32P- postlabeling assay, was increased by 4-fold, from 6.2 ± 2.2 nmol/mol dG in liver DNA of control rats to 28.5 ± 16.1 nmol/mol dG in the rats treated with BSO (p < 0.05). The formation of 8-oxodG in liver DNA was also increased as a result of BSO treatment, although the increase was not statistically significant. These results further support the endogenous origin of HNE-dG adducts and, more importantly, indicate a critical role that GSH plays in protecting against in vivo formation of the promutagenic cyclic DNA adducts derived from HNE.",
author = "Chung, {Fung Lung} and Despina Komninou and Lei Zhang and Raghu Nath and Jishen Pan and Shantu Amin and John Richie",
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Glutathione depletion enhances the formation of endogenous cyclic DNA adducts derived from t-4-hydroxy-2-nonenal in rat liver. / Chung, Fung Lung; Komninou, Despina; Zhang, Lei; Nath, Raghu; Pan, Jishen; Amin, Shantu; Richie, John.

In: Chemical Research in Toxicology, Vol. 18, No. 1, 01.01.2005, p. 24-27.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glutathione depletion enhances the formation of endogenous cyclic DNA adducts derived from t-4-hydroxy-2-nonenal in rat liver

AU - Chung, Fung Lung

AU - Komninou, Despina

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AU - Pan, Jishen

AU - Amin, Shantu

AU - Richie, John

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N2 - Earlier, we detected the cyclic adducts of deoxyguanosine (dG) derived from t-4-hydroxy-2-nonenal (HNE), a long chain α,β-unsaturated aldehyde (enal) product from oxidation of ω-6 polyunsaturated fatty acids, in tissue DNA of rats and humans as endogenous DNA damage. Recent evidence implicates the cyclic HNE adducts in human liver carcinogenesis. Because glutathione (GSH) protects against oxidative stress, we undertook a study to examine the effect of GSH depletion on the HNE-derived cyclic adducts in vivo. Four F344 rats were administered L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH biosynthesis, at 10 mM in drinking water for 2 weeks. Rats in the control group were given water only. Livers were harvested, and each liver was divided into portions for GSH and DNA adduct analyses. The BSO treatment depleted hepatic GSH by 77%; the GSH levels were reduced from 6.3 ± 0.3 in the control rats to 1.5 ± 0.1. μmol/g tissues in the treated group. The formation of HNE-dG adducts, analyzed by an HPLC-based 32P- postlabeling assay, was increased by 4-fold, from 6.2 ± 2.2 nmol/mol dG in liver DNA of control rats to 28.5 ± 16.1 nmol/mol dG in the rats treated with BSO (p < 0.05). The formation of 8-oxodG in liver DNA was also increased as a result of BSO treatment, although the increase was not statistically significant. These results further support the endogenous origin of HNE-dG adducts and, more importantly, indicate a critical role that GSH plays in protecting against in vivo formation of the promutagenic cyclic DNA adducts derived from HNE.

AB - Earlier, we detected the cyclic adducts of deoxyguanosine (dG) derived from t-4-hydroxy-2-nonenal (HNE), a long chain α,β-unsaturated aldehyde (enal) product from oxidation of ω-6 polyunsaturated fatty acids, in tissue DNA of rats and humans as endogenous DNA damage. Recent evidence implicates the cyclic HNE adducts in human liver carcinogenesis. Because glutathione (GSH) protects against oxidative stress, we undertook a study to examine the effect of GSH depletion on the HNE-derived cyclic adducts in vivo. Four F344 rats were administered L-buthionine-(S,R)-sulfoximine (BSO), a potent inhibitor of GSH biosynthesis, at 10 mM in drinking water for 2 weeks. Rats in the control group were given water only. Livers were harvested, and each liver was divided into portions for GSH and DNA adduct analyses. The BSO treatment depleted hepatic GSH by 77%; the GSH levels were reduced from 6.3 ± 0.3 in the control rats to 1.5 ± 0.1. μmol/g tissues in the treated group. The formation of HNE-dG adducts, analyzed by an HPLC-based 32P- postlabeling assay, was increased by 4-fold, from 6.2 ± 2.2 nmol/mol dG in liver DNA of control rats to 28.5 ± 16.1 nmol/mol dG in the rats treated with BSO (p < 0.05). The formation of 8-oxodG in liver DNA was also increased as a result of BSO treatment, although the increase was not statistically significant. These results further support the endogenous origin of HNE-dG adducts and, more importantly, indicate a critical role that GSH plays in protecting against in vivo formation of the promutagenic cyclic DNA adducts derived from HNE.

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