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Enhanced expression of pulmonary gamma-glutamylcysteine synthetase heavy subunit in rats exposed to cadmium aerosols.
Toxicol Appl Pharmacol. 2000 Mar 15; 163(3):249-59.TA

Abstract

This investigation sought to determine the effect of cadmium (Cd) aerosol exposure on the pulmonary expression of the heavy subunit (HS) of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in de novo synthesis of glutathione (GSH). Using Northern hybridization analysis, we demonstrated that CdO inhalation caused time- and dose-dependent increases in the steady-state levels of gamma-GCS-HS mRNA that were highly correlated with lung Cd burden. Observed increases in gamma-GCS-HS gene expression were maximal 2 h following a single aerosol exposure to Cd and appeared to be triggered by an oxidant stress, characterized by a decline in the reduced to oxidized glutathione ratio. Immunoblotting of proteins in lung extracts from treated and untreated animals produced a single protein band corresponding to a molecular weight of 73 kDa. Elevated levels of gamma-GCS-HS mRNA and gamma-GCS-HS protein in lungs of Cd-exposed animals were also accompanied by higher gamma-GCS enzymatic activity and elevations in glutathione (GSH). Immunohistochemical and in situ hybridization studies were used to identify compartments in the lung where Cd-induced expression of gamma-GCS-HS was localized. The most prominent staining for gamma-GCS-HS protein and gamma-GCS-HS mRNA was observed in the alveolar epithelium of Cd-exposed animals. Quantitative image analysis confirmed a good agreement between relative levels of protein and mRNA transcripts for gamma-GCS-HS. These observations suggest that resistance to Cd toxicity in the lung may reflect the ability of specific lung cells to upregulate gamma-GCS expression and increase de novo GSH synthesis as an adaptive response.

Authors+Show Affiliations

Biochemistry Department, University of Vermont College of Medicine, Burlington, Vermont, 05405-0068, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10702364

Citation

Shukla, G S., et al. "Enhanced Expression of Pulmonary Gamma-glutamylcysteine Synthetase Heavy Subunit in Rats Exposed to Cadmium Aerosols." Toxicology and Applied Pharmacology, vol. 163, no. 3, 2000, pp. 249-59.
Shukla GS, Chiu J, Hart BA. Enhanced expression of pulmonary gamma-glutamylcysteine synthetase heavy subunit in rats exposed to cadmium aerosols. Toxicol Appl Pharmacol. 2000;163(3):249-59.
Shukla, G. S., Chiu, J., & Hart, B. A. (2000). Enhanced expression of pulmonary gamma-glutamylcysteine synthetase heavy subunit in rats exposed to cadmium aerosols. Toxicology and Applied Pharmacology, 163(3), 249-59.
Shukla GS, Chiu J, Hart BA. Enhanced Expression of Pulmonary Gamma-glutamylcysteine Synthetase Heavy Subunit in Rats Exposed to Cadmium Aerosols. Toxicol Appl Pharmacol. 2000 Mar 15;163(3):249-59. PubMed PMID: 10702364.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced expression of pulmonary gamma-glutamylcysteine synthetase heavy subunit in rats exposed to cadmium aerosols. AU - Shukla,G S, AU - Chiu,J, AU - Hart,B A, PY - 2000/3/7/pubmed PY - 2000/4/15/medline PY - 2000/3/7/entrez SP - 249 EP - 59 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 163 IS - 3 N2 - This investigation sought to determine the effect of cadmium (Cd) aerosol exposure on the pulmonary expression of the heavy subunit (HS) of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme in de novo synthesis of glutathione (GSH). Using Northern hybridization analysis, we demonstrated that CdO inhalation caused time- and dose-dependent increases in the steady-state levels of gamma-GCS-HS mRNA that were highly correlated with lung Cd burden. Observed increases in gamma-GCS-HS gene expression were maximal 2 h following a single aerosol exposure to Cd and appeared to be triggered by an oxidant stress, characterized by a decline in the reduced to oxidized glutathione ratio. Immunoblotting of proteins in lung extracts from treated and untreated animals produced a single protein band corresponding to a molecular weight of 73 kDa. Elevated levels of gamma-GCS-HS mRNA and gamma-GCS-HS protein in lungs of Cd-exposed animals were also accompanied by higher gamma-GCS enzymatic activity and elevations in glutathione (GSH). Immunohistochemical and in situ hybridization studies were used to identify compartments in the lung where Cd-induced expression of gamma-GCS-HS was localized. The most prominent staining for gamma-GCS-HS protein and gamma-GCS-HS mRNA was observed in the alveolar epithelium of Cd-exposed animals. Quantitative image analysis confirmed a good agreement between relative levels of protein and mRNA transcripts for gamma-GCS-HS. These observations suggest that resistance to Cd toxicity in the lung may reflect the ability of specific lung cells to upregulate gamma-GCS expression and increase de novo GSH synthesis as an adaptive response. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/10702364/Enhanced_expression_of_pulmonary_gamma_glutamylcysteine_synthetase_heavy_subunit_in_rats_exposed_to_cadmium_aerosols_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041008X99988841 DB - PRIME DP - Unbound Medicine ER -