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ToxSci Advance Access originally published online on December 15, 2004
Toxicological Sciences 2005 84(1):157-166; doi:10.1093/toxsci/kfi057
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Toxicological Sciences vol. 84 no. 1 © Society of Toxicology 2005; all rights reserved.

Glutathione Reductase Inhibition and Methylated Arsenic Distribution in Cd1 Mice Brain and Liver

V. M. Rodríguez*, L. M. Del Razo{ddagger}, J. H. Limón-Pacheco{dagger}, M. Giordano*, L. C. Sánchez-Peña{ddagger}, Eileen Uribe-Querol{dagger}, G. Gutiérrez-Ospina{dagger} and M. E. Gonsebatt{dagger},1

* Instituto de Neurobiología, {dagger} Instituto de Investigaciones Biomédicas, UNAM, HP 70-228, Civdad Universitaria, 04510 DF, Mexico; and {ddagger} Sección de Toxicología, CINVESTAV-IPN, AP 14-740, 07000 DF, México

Received October 31, 2004; accepted December 5, 2004

Inorganic arsenic exposure via drinking water has been associated with cancer and serious injury in various internal organs, as well as with peripheral neuropathy and diverse effects in the nervous system. Alterations in memory and attention processes have been reported in exposed children, whereas adults acutely exposed to high amounts of inorganic arsenic showed impairments in learning, memory, and concentration. Glutathione (GSH) is extensively involved in the metabolism of inorganic arsenic, and both arsenite and its methylated metabolites have been shown to be potent inhibitors of glutathione reductase (GR) in vitro. Brain would be more susceptible to GR inhibition because of the decreased activities of superoxide dismutase (SOD) and catalase reported in this tissue. To investigate whether GR inhibition could be documented in vivo, we determined the activity and levels of GR in brain as well as in liver, the main organ of arsenic metabolism in mice exposed to 2.5, 5, or 10 mg/kg/day of sodium arsenite over a period of 9 days. In contrast to what has been observed in vitro, significant inhibition of the expression and activity of GR was observed only at the highest concentration used (10 mg/kg/day) in both organs. Although the disposition of arsenicals was higher in liver, significant amounts of inorganic and methylated arsenic forms were determined in the brain of exposed animals. The formation of monomethylarsenic (MMA) and dimethylarsenic (DMA) metabolites in the brain was confirmed by incubating brain slices for 24, 48, and 72 h with sodium arsenite.

Key Words: arsenite; biotransformation; glutathione reductase inhibition; brain.


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