Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 506-513 |
| Number of pages | 8 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 314 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 2005 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Consequences of abrupt glutathione depletion in murine Clara cells : Ultrastructural and biochemical investigations into the role of glutathione loss in naphthalene cytotoxicity. / Phimister, Andrew J.; Williams, Kurt J.; Van Winkle, Laura S.; Plopper, Charles.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 314, No. 2, 08.2005, p. 506-513.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Consequences of abrupt glutathione depletion in murine Clara cells
T2 - Ultrastructural and biochemical investigations into the role of glutathione loss in naphthalene cytotoxicity
AU - Phimister, Andrew J.
AU - Williams, Kurt J.
AU - Van Winkle, Laura S.
AU - Plopper, Charles
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.105.084533
DO - 10.1124/jpet.105.084533
M3 - Article
VL - 314
SP - 506
EP - 513
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -