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Gamma-glutamyl transpeptidase null mice fail to develop tolerance to coumarin-induced Clara cell toxicity
Jeffrey D Vassallo1, Rhonda S Kaetzel, Stephanie L Born
1Miami Valley Innovation Center, The Procter and Gamble Company, Cincinnati, OH 45252, USA. jeff.vassallo@bms.com
Abstract:
Coumarin was used as a model Clara cell toxicant to test the hypothesis that tolerance to injury requires increased gamma-glutamyl transpeptidase (GGT) activity. Wildtype (GGT(+/+)) and GGT-deficient (GGT(-/-)) mice on a C57BL/6/129SvEv hybrid background were dosed orally with corn oil (vehicle) or coumarin (200 mg/kg). In vehicle-treated mice, Clara cell secretory protein (CC10) expression was distributed throughout the bronchiolar epithelium. After one dose of coumarin, CC10 expression was dramatically reduced and the bronchiolar epithelium was devoid of Clara cells in GGT(+/+) and GGT(-/-) mice. In wildtype mice, 9 doses of coumarin produced tolerance, characterized as a renewed bronchiolar epithelium with Clara cells expressing CC10 along with a 40% increase in total glutathione (GSH) and a 7-fold increase in GGT activity in the lung. In contrast, tolerance was not observed in GGT(-/-) mice. To assess whether changes in whole lung levels of GSH and GGT activity reflect Clara cell specific changes an enriched population of cells was isolated from female wildtype B6C3F1 mice made tolerant to coumarin. Compared to Clara cells from control mice, GSH and GGT activity increased 3- and 13-fold, respectively. Collectively, these data suggest Clara cell tolerance to coumarin toxicity requires increased GGT activity favoring enhanced GSH synthesis.
Insights
Developing tolerance to coumarin toxicity in Clara cells requires increased gamma-glutamyl transpeptidase (GGT) activity, which enhances glutathione (GSH) synthesis for cellular protection.
Area of Science:
- Toxicology
- Cellular Biology
- Pulmonary Medicine
Background:
- Coumarin is a model toxicant for studying Clara cell injury.
- Gamma-glutamyl transpeptidase (GGT) plays a role in cellular defense mechanisms.
- Understanding tolerance mechanisms is crucial for mitigating chemical-induced lung damage.
Purpose of the Study:
- To investigate the role of GGT activity in the development of tolerance to coumarin-induced Clara cell toxicity.
- To determine if increased GGT activity is necessary for Clara cell protection against coumarin.
Main Methods:
- Comparison of coumarin toxicity and tolerance development in wildtype (GGT(+/+)) and GGT-deficient (GGT(-/-)) mice.
- Assessment of Clara cell secretory protein (CC10) expression and bronchiolar epithelium integrity.
- Measurement of lung and isolated Clara cell glutathione (GSH) and GGT activity levels.
Main Results:
- Coumarin induced acute Clara cell injury in both GGT(+/+) and GGT(-/-) mice.
- Wildtype mice developed tolerance to coumarin with increased lung GGT activity and GSH levels after repeated dosing.
- GGT-deficient mice did not develop tolerance, showing significantly lower GSH and GGT activity in lung tissue and isolated Clara cells.
- Isolated Clara cells from tolerant wildtype mice showed a 13-fold increase in GGT activity and a 3-fold increase in GSH.
Conclusions:
- Clara cell tolerance to coumarin toxicity is dependent on increased GGT activity.
- Elevated GGT activity enhances glutathione synthesis, providing protection against coumarin-induced injury.
- GGT is essential for developing adaptive responses and tolerance to specific chemical toxicants in the lung.
