Toxicology Letters 110 (1999) 1 – 9 Induction of glutamate-cysteine ligase (-glutamylcysteine synthetase) in the brains of adult female mice subchronically exposed to methylmercury Sally A. Thompson a,b,1 , Collin C. White b , Cecile M. Krejsa b , Dolores Diaz b , James S. Woods b , David L. Eaton b , Terrance J. Kavanagh b, * a Department of Comparatie Medicine, Uniersity of Washington, Seattle, WA, USA b Department of Eniromental Health, and NIEH Center for Ecogenetics and Eniromental Health, Uniersity of Washington, Seattle, WA, USA Received 3 September 1998; received in revised form 11 June 1999; accepted 15 June 1999 Abstract Methylmercury (MeHg) is widely known for its potent neurotoxic properties. One proposed mechanism of action of MeHg relates to its high affinity for sulfhydryl groups, especially those found on glutathione (GSH) and proteins. Previous studies have shown that acute MeHg exposure results in an increase in the mRNA for the rate-limiting enzyme in GSH synthesis, glutamate-cysteine ligase (GLCL) (also known as -glutamylcysteine synthetase). In this study, we evaluated the effects of subchronic (12-week) MeHg exposure at 0, 3 or 10 ppm in the drinking water on GSH levels, GLCL catalytic (GLCLC) and regulatory subunit mRNA and protein levels, and GLCL activity in brain, liver and kidney tissue of C57Bl/6 female mice. Contrary to previous findings in rats, there were no changes in GSH concentration in any of the tissues examined. However, there was an increase in GLCLC protein in the brain, which was accompanied by a 30% increase in GLCL activity. We conclude that up-regulation of GSH synthetic capacity in the brains of mice is a sensitive biomarker of subchronic MeHg exposure. © 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Glutamate-cysteine ligase; -Glutamylcysteine synthetase; Glutathione; Methylmercury; Mice www.elsevier.com/locate/toxlet 1. Introduction Methylmercury (MeHg) is a heavy metal of widespread environmental concern. Exposure to MeHg has been associated with toxicity to the nervous system, the kidneys and the developing fetus. The pathophysiological effects of MeHg on tissues are partially related to its high affinity for * Corresponding author. Tel.: +1-206-685-8479; fax: +1- 206-685-4696. E-mail address: tjkav@u.washington.edu (T.J. Kavanagh) 1 Present address: Targeted Genetics Corporation, 1100 Olive Way, Suite 100, Seattle, WA 98101, USA. 0378-4274/99/$ - see front matter © 1999 Published by Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(99)00133-2