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Carcinogenesis Advance Access published online on September 14, 2005
Carcinogenesis, doi:10.1093/carcin/bgi222
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 1, 2005
Revised August 30, 2005
Accepted September 3, 2005

CANCER BIOLOGY

Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice

Ramune Reliene 1 and Robert H. Schiestl 1*

1 Department of Pathology, Geffen School of Medicine and School of Public Health, UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90024; Department of Environmental Health, Geffen School of Medicine and School of Public Health, UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90024; Department of Radiation Oncology, Geffen School of Medicine and School of Public Health, UCLA, 650 Charles E. Young Drive South, Los Angeles, CA 90024

* To whom correspondence should be addressed.
Robert H. Schiestl, E-mail: rschiestl{at}mednet.ucla.edu


  Abstract

Oxidative stress and genomic rearrangements play a role in cancer development. L-buthionine-sulfoximine (BSO) induces oxidative stress in a cell by irreversibly inhibiting {gamma}-glutamylcysteine synthetase ({gamma}-GCS), 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 prooxidant 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. Two 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. Twenty mM BSO 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.

Keywords: glutathione; buthionine sulfoximine; oxidative stress; mouse; in vivo; pun reversions; DNA deletions; 8-OH deoxyguanosine; N-Acetyl cysteine.
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