Transformation of liver cells by 3-methylcholanthrene potentiates oxidative stress via the downregulation of glutathione synthesis

Sou Hyun Kim, Dahye Yoon, Yun-Hee Lee, Jaewon Lee, Nam Deuk Kim, Suhkmann Kim, Young Suk Jung

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants resulting from the incomplete combustion of organic materials in the environment. The primary concern for the hazardous effect of PAHs is their ability to activate the pathway linked to the aryl hydrocarbon receptor (AhR) and lead to carcinogenesis. While previous research has demonstrated that oxidative stress plays a key role in the AhR-dependent toxic response, the effect of PAHs on the biosynthesis of glutathione (GSH), which is a powerful endogenous antioxidant, has not been extensively investigated. In the present study, we utilized a global metabolomic approach, via high resolution magic angle spinning nuclear magnetic resonance spectroscopy, and identified significant metabolome differences between non-tumorigenic liver cells (BNL CL.2; CL2) and transformed liver cells (BNL 1MEA. 7R.1; 1MEA) chronically exposed to 3-methylcholanthrene (3MC), a well-known carcinogenic PAH. A significant change that was observed, was a lower GSH level in 1MEA cells compared with that in CL2 cells. This was contrasted by increased levels of precursor metabolites for GSH synthesis, such as S-adenosylmethionine and cysteine. These changes were accompanied by a significantly reduced expression of γ-glutamylcysteine ligase (GCL), known to be the rate-limiting step of GSH synthesis. Furthermore, the protein level of cysteine dioxygenase was downregulated; however, the concentration of taurine was unaltered. Therefore, the present study demonstrated that cells transformed by chronic exposure to 3MC exhibited inhibition of GSH biosynthesis by suppression of GCL protein expression and reduction of cysteine availability, which may subsequently render cells vulnerable to oxidative stress.

Original languageEnglish
Pages (from-to)2011-2017
Number of pages7
JournalInternational journal of molecular medicine
Volume40
Issue number6
DOIs
Publication statusPublished - 2017 Dec 1

Fingerprint

Methylcholanthrene
Glutathione
Oxidative Stress
Down-Regulation
Polycyclic Aromatic Hydrocarbons
Liver
Aryl Hydrocarbon Receptors
Ligases
Cysteine
Cysteine Dioxygenase
S-Adenosylmethionine
Metabolomics
Metabolome
Poisons
Taurine
Carcinogenesis
Proteins
Magnetic Resonance Spectroscopy
Antioxidants
Research

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Kim, Sou Hyun ; Yoon, Dahye ; Lee, Yun-Hee ; Lee, Jaewon ; Kim, Nam Deuk ; Kim, Suhkmann ; Jung, Young Suk. / Transformation of liver cells by 3-methylcholanthrene potentiates oxidative stress via the downregulation of glutathione synthesis. In: International journal of molecular medicine. 2017 ; Vol. 40, No. 6. pp. 2011-2017.
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abstract = "Polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants resulting from the incomplete combustion of organic materials in the environment. The primary concern for the hazardous effect of PAHs is their ability to activate the pathway linked to the aryl hydrocarbon receptor (AhR) and lead to carcinogenesis. While previous research has demonstrated that oxidative stress plays a key role in the AhR-dependent toxic response, the effect of PAHs on the biosynthesis of glutathione (GSH), which is a powerful endogenous antioxidant, has not been extensively investigated. In the present study, we utilized a global metabolomic approach, via high resolution magic angle spinning nuclear magnetic resonance spectroscopy, and identified significant metabolome differences between non-tumorigenic liver cells (BNL CL.2; CL2) and transformed liver cells (BNL 1MEA. 7R.1; 1MEA) chronically exposed to 3-methylcholanthrene (3MC), a well-known carcinogenic PAH. A significant change that was observed, was a lower GSH level in 1MEA cells compared with that in CL2 cells. This was contrasted by increased levels of precursor metabolites for GSH synthesis, such as S-adenosylmethionine and cysteine. These changes were accompanied by a significantly reduced expression of γ-glutamylcysteine ligase (GCL), known to be the rate-limiting step of GSH synthesis. Furthermore, the protein level of cysteine dioxygenase was downregulated; however, the concentration of taurine was unaltered. Therefore, the present study demonstrated that cells transformed by chronic exposure to 3MC exhibited inhibition of GSH biosynthesis by suppression of GCL protein expression and reduction of cysteine availability, which may subsequently render cells vulnerable to oxidative stress.",
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Transformation of liver cells by 3-methylcholanthrene potentiates oxidative stress via the downregulation of glutathione synthesis. / Kim, Sou Hyun; Yoon, Dahye; Lee, Yun-Hee; Lee, Jaewon; Kim, Nam Deuk; Kim, Suhkmann; Jung, Young Suk.

In: International journal of molecular medicine, Vol. 40, No. 6, 01.12.2017, p. 2011-2017.

Research output: Contribution to journalArticle

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T1 - Transformation of liver cells by 3-methylcholanthrene potentiates oxidative stress via the downregulation of glutathione synthesis

AU - Kim, Sou Hyun

AU - Yoon, Dahye

AU - Lee, Yun-Hee

AU - Lee, Jaewon

AU - Kim, Nam Deuk

AU - Kim, Suhkmann

AU - Jung, Young Suk

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AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants resulting from the incomplete combustion of organic materials in the environment. The primary concern for the hazardous effect of PAHs is their ability to activate the pathway linked to the aryl hydrocarbon receptor (AhR) and lead to carcinogenesis. While previous research has demonstrated that oxidative stress plays a key role in the AhR-dependent toxic response, the effect of PAHs on the biosynthesis of glutathione (GSH), which is a powerful endogenous antioxidant, has not been extensively investigated. In the present study, we utilized a global metabolomic approach, via high resolution magic angle spinning nuclear magnetic resonance spectroscopy, and identified significant metabolome differences between non-tumorigenic liver cells (BNL CL.2; CL2) and transformed liver cells (BNL 1MEA. 7R.1; 1MEA) chronically exposed to 3-methylcholanthrene (3MC), a well-known carcinogenic PAH. A significant change that was observed, was a lower GSH level in 1MEA cells compared with that in CL2 cells. This was contrasted by increased levels of precursor metabolites for GSH synthesis, such as S-adenosylmethionine and cysteine. These changes were accompanied by a significantly reduced expression of γ-glutamylcysteine ligase (GCL), known to be the rate-limiting step of GSH synthesis. Furthermore, the protein level of cysteine dioxygenase was downregulated; however, the concentration of taurine was unaltered. Therefore, the present study demonstrated that cells transformed by chronic exposure to 3MC exhibited inhibition of GSH biosynthesis by suppression of GCL protein expression and reduction of cysteine availability, which may subsequently render cells vulnerable to oxidative stress.

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