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TOXICOLOGY

Consequences of Abrupt Glutathione Depletion in Murine Clara Cells: Ultrastructural and Biochemical Investigations into the Role of Glutathione Loss in Naphthalene Cytotoxicity

Department of Molecular Biosciences (A.J.P.) and Anatomy, Physiology, and Cell Biology (L.S.V.W., C.G.P.), School of Veterinary Medicine, University of California, Davis, Davis, CA; and Department of Pathobiology and Diagnostic Investigation (K.J.W.), G380 Veterinary Medical Center, Michigan State University, East Lansing, Michigan

Glutathione plays many critical roles within the cell, including offering protection from reactive chemicals. The bioactivated toxicant naphthalene forms chemically reactive intermediates that can deplete glutathione and covalently bind to cellular proteins. Naphthalene selectively injures the nonciliated epithelial cells of the intrapulmonary airways (i.e., Clara cells). This study attempted to define what role glutathione loss plays in naphthalene cytotoxicity by comparing Swiss-Webster mice treated with naphthalene with those treated with the glutathione depletor diethylmaleate. High-resolution imaging techniques were used to evaluate acute changes in Clara cell ultrastructure, membrane permeability, and cytoskeleton structure. A single dose of either diethylmaleate (1000 mg/kg) or naphthalene (200 mg/kg) caused similar glutathione losses in intrapulmonary airways (<20% of control). Diethylmaleate did not increase membrane permeability, disrupt mitochondria, or lead to cell death— hallmark features of naphthalene cytotoxicity. However, diethylmaleate treatment did cause Clara cell swelling, plasma membrane blebs, and actin cytoskeleton disruptions similar to naphthalene treatment. Structural changes in mitochondria and Golgi bodies also were noted. Changes in ATP levels were measured as an indication of overall cell function, in isolated airway explants incubated with diethylmaleate, naphthalene, or naphthalene metabolites in vitro. Only the reactive metabolites of naphthalene caused significant ATP losses. Unlike the lethal injury caused by naphthalene, the disruptive cellular changes associated with glutathione loss from diethylmaleate seemed to be reversible after recovery of glutathione levels. This suggests that glutathione depletion may be responsible for some aspects of naphthalene cytotoxicity, but it is not sufficient to cause cell death without further stresses.

Address correspondence to: Dr. Andrew J. Phimister, Department of Molecular Biosciences, University of California, Davis, CA 95616. E-mail: aphimister{at}ucdavis.edu

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