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Vol. 300, Issue 3, 768-776, March 2002

Thalidomide Modulates Nuclear Redox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb

Jason M. Hansen, Katie K. Harris, Martin A. Philbert and Craig Harris

University of Michigan, Department of Environmental Health Sciences Toxicology Program, Ann Arbor, Michigan

Thalidomide produces numerous birth defects, the most notable being phocomelia. Mechanisms behind thalidomide-induced malformations have not been fully elucidated, although recent evidence suggests a role for reactive oxygen species. A thalidomide-resistant (rat) and -sensitive (rabbit) species were used to compare potential inherent differences related to oxidative stress that may provide a more definitive understanding of mechanisms of thalidomide embryopathy. Limb bud cells (LBCs) were removed from the rat and rabbit embryo, dissociated, and plated in culture for 24 h. A fluorescence (6-carboxy-2',7'-dichlorofluorescin diacetate; DCF) assay for oxidative stress was used with varying concentrations of thalidomide (5-100 µM). Thalidomide (100 µM) showed a 6-fold greater production of oxidative stress in rabbit cultures than in rat. Lower concentrations (50 and 25 µM) also showed a significant increase in reactive oxygen species. Confocal microscopy revealed DCF fluorescence preferentially in rabbit LBC nuclei compared with the uniform distribution of DCF fluorescence in rat LBC. Localization of glutathione (GSH) was determined using 5-chloromethylfluorescein diacetate fluorescent confocal microscopy. In rat cultures, significant thalidomide-induced GSH depletion was detected in the cytosol but the nuclei maintained its GSH content, but rabbit LBC showed significant GSH depletion in both compartments. GSH depletion was confirmed by high-performance liquid chromatography analysis. These observations provide evidence that thalidomide preferentially produces oxidative stress in the thalidomide-sensitive species but not the thalidomide-resistant species. Nuclear GSH content in the rabbit LBC is selectively modified and indicates a shift in the nuclear redox environment. Redox shifts in the nucleus may result in the misregulation of transcription factor/DNA interactions and cause defective growth and development.

0022-3565/02/3003-0768$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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