Carcinogenesis Advance Access originally published online on September 14, 2005
Carcinogenesis 2006 27(2):240-244; doi:10.1093/carcin/bgi222
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis Vol.27 no.2 © Oxford University Press 2005; all rights reserved.
Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice
Department of Pathology, Department of Environmental Health and Department of Radiation Oncology, Geffen School of Medicine and School of Public Health, UCLA, Los Angeles, CA 90024, USA
* To whom correspondence should be addressed at: Department of Pathology, UCLA School of Medicine, 650 Charles E. Young Drive South, Los Angeles, CA 90024, USA. Tel: 310 267 2087; Fax: 310 267 2578; Email: rschiestl{at}mednet.ucla.edu
Oxidative stress and genomic rearrangements play a role in cancer development. L-Buthionine-sulfoximine (BSO) induces oxidative stress in a cell by irreversibly inhibiting 
-glutamylcysteine synthetase, an essential enzyme for the synthesis of glutathione (GSH). We postulated that oxidative stress induced by GSH depletion might lead to genomic rearrangements, such as DNA deletions, and that counteracting such pro-oxidant conditions by the exogenous antioxidant N-acetyl-L-cysteine (NAC), might suppress DNA deletions. Therefore, we determined the frequency of 70 kb DNA deletions and thiol levels in mouse fetuses exposed to BSO (alone or in combination with NAC) via drinking water given to female mice during gestation. BSO treatment resulted in a significantly increased frequency of DNA deletions and decreased concentrations of GSH and cysteine. An amount of 2 mM BSO treatment resulted in a 30% higher DNA deletion frequency, 45% lower GSH and 27% lower cysteine levels, when compared with the untreated control and 20 mM BSO treatment caused a 40% higher DNA deletion frequency, 70% lower GSH and 55% lower cysteine levels. In combination BSO and NAC resulted in reduced levels of GSH consistent with the effect of BSO; however, cysteine levels increased and the frequency of DNA deletions was within the normal range. Thus, NAC protected against genome rearrangements caused by GSH depletion. This study showed that lowering the concentrations of thiol antioxidants results in DNA deletions that may play a role in carcinogenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Azad, V. Vallyathan, L. Wang, V. Tantishaiyakul, C. Stehlik, S. S. Leonard, and Y. Rojanasakul S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation: A NOVEL ANTIAPOPTOTIC MECHANISM THAT SUPPRESSES APOPTOSIS J. Biol. Chem., November 10, 2006; 281(45): 34124 - 34134. [Abstract] [Full Text] [PDF]
|
|