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

doi:10.3892/ijmm.2017.3184

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

Authors:
- Sou Hyun Kim
- Dahye Yoon
- Yun-Hee Lee
- Jaewon Lee
- Nam Deuk Kim
- Suhkmann Kim
- Young-Suk Jung
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Affiliations: College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea, Department of Chemistry, Center for Proteome Biophysics and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic of Korea, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea
Published online on: October 11, 2017 https://doi.org/10.3892/ijmm.2017.3184
Pages: 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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