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Biological Chemistry

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Glutathione dysregulation and the etiology and progression of human diseases

Nazzareno Ballatori
  • 1Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
/ Suzanne M. Krance
  • 2Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
/ Sylvia Notenboom
  • 3Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
/ Shujie Shi
  • 4Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
/ Kim Tieu
  • 5Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
/ Christine L. Hammond
  • 6Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA
Published Online: 2009-01-23 | DOI: https://doi.org/10.1515/BC.2009.033


Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

Keywords: aging; cancer; cardiovascular diseases; glutathione; metabolic diseases; neurodegenerative diseases

Corresponding author

Received: 2008-10-22

Accepted: 2008-12-12

Published Online: 2009-01-23

Published in Print: 2009-03-01

Citation Information: Biological Chemistry. Volume 390, Issue 3, Pages 191–214, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2009.033, January 2009

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Clinical and Experimental Pharmacology and Physiology, 2012, Volume 39, Number 3, Page 256
A. Kawamoto, N. Sugano, M. Motohashi, S. Matsumoto, and K. Ito
Journal of Periodontal Research, 2012, Volume 47, Number 5, Page 593
Özge Çevik, Rabia Oba, Çağlar Macit, Şule Çetinel, Özlem Tuğçe Çilingir Kaya, Emre Şener, and Göksel Şener
Burns, 2012, Volume 38, Number 6, Page 861
Moonhee Lee, Byoung-Mok Kwon, Kyoungho Suk, Edith McGeer, and Patrick L. McGeer
Journal of Neuroimmune Pharmacology, 2012, Volume 7, Number 1, Page 173
Francesco Galli, Andrea Battistoni, Roberto Gambari, Alfonso Pompella, Alessandra Bragonzi, Francesca Pilolli, Luigi Iuliano, Marta Piroddi, Maria Cristina Dechecchi, and Giulio Cabrini
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012, Volume 1822, Number 5, Page 690
Meri P. Nantz, Cheryl A. Rowe, Catherine E. Muller, Rebecca A. Creasy, Joy M. Stanilka, and Susan S. Percival
Clinical Nutrition, 2012, Volume 31, Number 3, Page 337
Kevin G. Becker and Stephen T. Schultz
Medical Hypotheses, 2010, Volume 74, Number 1, Page 7
P. S. Hole, R. L. Darley, and A. Tonks
Blood, 2011, Volume 117, Number 22, Page 5816
João M.N. Duarte, Hongxia Lei, Vladimír Mlynárik, and Rolf Gruetter
NeuroImage, 2012, Volume 61, Number 2, Page 342
Avishek Ganguly, Paramita Chakraborty, Kaushik Banerjee, Shilpak Chatterjee, Soumya Basu, Avijit Sarkar, Mitali Chatterjee, and Soumitra Kumar Choudhuri
BioMetals, 2012, Volume 25, Number 1, Page 149
Jihyun Park and Jihoe Kim
The Protein Journal, 2012, Volume 31, Number 2, Page 158
Anna Sparatore, Giancarlo Santus, Daniela Giustarini, Ranieri Rossi, and Piero Del Soldato
Expert Review of Clinical Pharmacology, 2011, Volume 4, Number 1, Page 109
Tuğrul Çakır, Erkan Özkan, Ender Dulundu, Ümit Topaloğlu, Ahmet Özer Şehirli, Feriha Ercan, Emre Şener, and Göksel Şener
Journal of Pharmacy and Pharmacology, 2011, Volume 63, Number 12, Page 1566
Magdalena L. Circu and Tak Yee Aw
Free Radical Research, 2011, Volume 45, Number 11-12, Page 1245
Kerim Çayır, Ali Karadeniz, Nejdet Şimşek, Serap Yıldırım, Emre Karakuş, Adem Kara, Hürrem Turan Akkoyun, and Emin Şengül
Journal of Medicinal Food, 2011, Volume 14, Number 10, Page 1254
Vanna Z.Y. Ding, Sean S.H. Dawson, Lewis W.Y. Lau, DongJin R. Lee, Natalie J. Galant, David H. Setiadi, Balázs Jójárt, Milán Szöri, Zoltán Mucsi, Béla Viskolcz, Svend J. Knak Jensen, and Imre G. Csizmadia
Chemical Physics Letters, 2011, Volume 507, Number 1-3, Page 168
Harry Quon, Traci Leong, Robert Haselow, Bruce Leipzig, Jay Cooper, and Arlene Forastiere
International Journal of Radiation Oncology*Biology*Physics, 2011, Volume 81, Number 3, Page 719
Dilip Shah, Ravi Kiran, Ajay Wanchu, and Archana Bhatnagar
Immunology Letters, 2010, Volume 129, Number 1, Page 7
Hui-Yun Wen, Hai-Qing Dong, Wen-juan Xie, Yong-Yong Li, Kang Wang, Giovanni M. Pauletti, and Dong-Lu Shi
Chemical Communications, 2011, Volume 47, Number 12, Page 3550
Nadezda Apostolova, Remedios Garcia-Bou, Antonio Hernandez-Mijares, Raul Herance, Milagros Rocha, and Victor M. Victor
Pharmaceutical Research, 2011, Volume 28, Number 11, Page 2910
Paolo Bergamo, Marta Gogliettino, Gianna Palmieri, Ennio Cocca, Francesco Maurano, Rosita Stefanile, Marco Balestrieri, Giuseppe Mazzarella, Chella David, and Mauro Rossi
Molecular Nutrition & Food Research, 2011, Volume 55, Number S2, Page S248
Mukaddes Eşrefoğlu, Mehmet Gül, Burhan Ateş, and Ali Erdoğan
Fundamental & Clinical Pharmacology, 2011, Volume 25, Number 5, Page 580
Minori Koga, Anthony V. Serritella, Marcus M. Messmer, Akiko Hayashi-Takagi, Lynda D. Hester, Solomon H. Snyder, Akira Sawa, and Thomas W. Sedlak
Biochemical and Biophysical Research Communications, 2011, Volume 409, Number 4, Page 596
Björn Goldenbogen, Nicolai Brodersen, Andrea Gramatica, Martin Loew, Jürgen Liebscher, Andreas Herrmann, Holger Egger, Bastian Budde, and Anna Arbuzova
Langmuir, 2011, Volume 27, Number 17, Page 10820
Alberto J. Montero and Jacek Jassem
Drugs, 2011, Volume 71, Number 11, Page 1385
Y. Kamide, M. Utsugi, K. Dobashi, A. Ono, T. Ishizuka, T. Hisada, Y. Koga, K. Uno, J. Hamuro, and M. Mori
Allergy, 2011, Volume 66, Number 9, Page 1183
Sarah E. Bohndiek, Mikko I. Kettunen, De-en Hu, Brett W. C. Kennedy, Joan Boren, Ferdia A. Gallagher, and Kevin M. Brindle
Journal of the American Chemical Society, 2011, Volume 133, Number 30, Page 11795
Haolin Chen, Liang Zhou, Chieh-Yin Lin, Matthew C. Beattie, June Liu, and Barry R. Zirkin
Molecular and Cellular Endocrinology, 2010, Volume 323, Number 2, Page 147
Daniela Giustarini, Isabella Dalle-Donne, Aldo Milzani, and Ranieri Rossi
Mechanisms of Ageing and Development, 2011, Volume 132, Number 4, Page 141
Suzanne H. Michel, Asim Maqbool, Maria D. Hanna, and Maria Mascarenhas
Pediatric Clinics of North America, 2009, Volume 56, Number 5, Page 1123
Daniel I. Chu, Rizal Lim, Stanley Heydrick, Melanie L. Gainsbury, Rami Abdou, Laura D’Addese, Karen L. Reed, Arthur F. Stucchi, and James M. Becker
Surgery, 2011, Volume 149, Number 6, Page 801
Daniela Giustarini, Isabella Dalle-Donne, Aldo Milzani, and Ranieri Rossi
Analytical Biochemistry, 2011, Volume 415, Number 1, Page 81
Jin-Ju Jeong, Tal-Soo Ha, and Ji-Hoe Kim
BMB Reports, 2011, Volume 44, Number 3, Page 170
Doreen Jia Yi Ng, Kishore Kumar Pasikanti, and Eric Chun Yong Chan
Metabolomics, 2011, Volume 7, Number 2, Page 155
Toby B. Cole, Gennaro Giordano, Aila L. Co, Isaac Mohar, Terrance J. Kavanagh, and Lucio G. Costa
Journal of Toxicology, 2011, Volume 2011, Page 1
Jeung-Min Lee, Jae-Hee Park, Won-Mi Chu, Yi-Mook Yoon, Eun-Ju Park, and Hae-Ryong Park
Journal of Life Science, 2011, Volume 21, Number 1, Page 62
Cynthia A. Massaad and Eric Klann
Antioxidants & Redox Signaling, 2011, Volume 14, Number 10, Page 2013
Jan Lewerenz and Pamela Maher
Antioxidants & Redox Signaling, 2011, Volume 14, Number 8, Page 1449
Chunchen Lin, Vladimir L. Kolossov, Gene Tsvid, Lisa Trump, Jennifer Jo Henry, Jerrod L. Henderson, Laurie A. Rund, Paul J.A. Kenis, Lawrence B. Schook, H. Rex Gaskins, and Gregory Timp
Integr. Biol., 2011, Volume 3, Number 3, Page 208
Cristovao F. Lima, Cristina Pereira-Wilson, and Suresh I. S. Rattan
Molecular Nutrition & Food Research, 2011, Volume 55, Number 3, Page 430
Shambhunath Choudhary, Kusum Rathore, and Hwa-Chain Robert Wang
Journal of Cancer Research and Clinical Oncology, 2011, Volume 137, Number 3, Page 471
Rodrigo Lorenzi, Michael Everton Andrades, Rafael Calixto Bortolin, Ryoji Nagai, Felipe Dal-Pizzol, and José Cláudio Fonseca Moreira
Cardiovascular Toxicology, 2010, Volume 10, Number 4, Page 244
Isaac G. Onyango, Jin-Young Ahn, Jeremy B. Tuttle, James P. Bennett Jr, and Russell H. Swerdlow
Journal of Neurochemistry, 2010, Volume 114, Number 6, Page 1605
M. F. Leite, A. De Lima, M. M. Massuyama, and R. Otton
International Endodontic Journal, 2010, Volume 43, Number 11, Page 959
Shambhunath Choudhary, Kusum Rathore, and Hwa-Chain Robert Wang
Anti-Cancer Drugs, 2010, Volume 21, Number 9, Page 831
Jolanta Idkowiak‑Baldys, Aintzane Apraiz, Li Li, Mehrdad Rahmaniyan, Christopher J. Clarke, Jacqueline M. Kraveka, Aintzane Asumendi, and Yusuf A. Hannun
Biochemical Journal, 2010, Volume 427, Number 2, Page 265
A Madeo, M Vinciguerra, R Lappano, M Galgani, A Gasperi-Campani, M Maggiolini, and A M Musti
Oncogene, 2010, Volume 29, Number 7, Page 978
Zeng-Chun Ma, Qian Hong, Yu-Guang Wang, Hong-Ling Tan, Cheng-Rong Xiao, Qian-De Liang, Bo-Li Zhang, and Yue Gao
Biological & Pharmaceutical Bulletin, 2010, Volume 33, Number 1, Page 29
Theresa W. Gauthier, Julie A. Kable, Leandrea Burwell, Claire D. Coles, and Lou Ann S. Brown
Alcoholism: Clinical and Experimental Research, 2010, Volume 34, Number 1, Page 123

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