期刊
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
卷 83, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.etap.2020.103576
关键词
Acrolein; In vitro dosimetry; Protein carbonylation; Glutathione; NHBE cells; NCI-H292 cells
资金
- FDA
Accurate dosimetry is crucial for assessing xenobiotic toxicity and comparing responses in different test systems. This study used acrolein as a model toxicant and developed a new method to indirectly estimate its intracellular uptake. Findings showed that normal human bronchial epithelial cells were more sensitive to acrolein exposure compared to mucoepidermoid pulmonary carcinoma cells, with GSH depletion and conjugation identified as primary adverse events associated with cytotoxicity.
Establishing accurate dosimetry is important for assessing the toxicity of xenobiotics as well as for comparing responses between different test systems. In this study, we used acrolein as a model toxicant and defined the concentration-response relationships of the key adverse responses in normal human bronchial epithelial (NHBE) cells and human mucoepidermoid pulmonary carcinoma (NCI-H292) cells. Direct trace analysis of intracellular free acrolein is extremely challenging, if not impossible. Therefore, we developed a new method for indirectly estimating the intracellular uptake of acrolein. A 10-min treatment was employed to capture the rapid occurrence of the key alkylation reactions of acrolein. Responses, including protein carbonylation, GSH depletion, and GSH-acrolein (GSH-ACR) adduct formation, were all linearly correlated with acrolein uptake in both cell types. Compared to the NCI-H292 mucoepidermoid carcinoma cells, NHBE cells were more sensitive to acrolein exposure. Furthermore, results from the time-course studies demonstrated that depletion and conjugation of GSH were the primary adverse events and directly associated with the cytotoxicity induced by acrolein. In summary, these data suggest that cell susceptibility to acrolein exposure is closely associated with acrolein uptake and formation of GSH-ACR adducts. The dosimetric analysis presented in this study may provide useful information for computational modeling and risk assessment of acrolein using different test systems.
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