Thiol-aldehyde adducts and tobacco smoke toxicity
Abstracts
Initial Award Abstract |
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It is well appreciated that cigarette smoking is associated with cancer, cardiovascular and pulmonary diseases such as chronic bronchitis and emphysema. Although the relationships between the variety of diseases and smoking are well established, the biochemical mechanisms underlying the effects of smoking are not well understood. It is important to understand these biochemical mechanisms to treat the diseases associated with smoking. There are many harmful components in cigarette smoke (CS) that can damage biomolecules such as lipids, proteins and nucleic acid present in cells, eventually leading to cell death. Antioxidants such as vitamin C, glutathione, and uric acid can protect us from damage induced by cigarette smoke. Of these antioxidants, glutathione is present in the largest amounts within cells and is rapidly depleted in the presence of tobacco smoke. The reason for the rapid depletion of glutathione is that it contains a thiol group (-SH group) in it, which is very susceptible to damage by smoke. Also, proteins contain -SH groups, which can be damaged easily leading to loss in protein function. Administration of thiol group-containing drugs (such as N-acetyl cysteine) may prevent the loss of protein thiol groups noted in smokers.
Until now the products formed between glutathione and CS have not been identified. However, the preliminary results presented in this proposal show that in test tube experiments, a majority of glutathione forms an irreversible adduct with acrolein, a very reactive component present in CS. This proposal intends to measure the formation of glutathione-acrolein adducts in cells lining the surfaces of the lung (pulmonary epithelial cells). The identification of these adducts will help to emphasize that the reactions are also relevant physiologically. Identification of these adducts will help us in the future to design studies to determine the formation and clearance of these adducts in smokers. These studies are essential since glutathione-acrolein adducts are themselves observed to be toxic in animals leading to kidney failure. The proposal also intends to identify the effect of CS on –SH containing proteins involved in cell signaling pathways. For example, the enzyme protein tyrosine phosphatase 1B (PTP 1B) regulates the activity of important receptors such as the epidermal growth factor receptor and the insulin receptor. This phosphatase also regulates the activity of an oncogene kinase, which suggests it may play a role in tumor supression. Studying the effect of the components of CS on the activity of this critical enzyme will help determine how smoking can interfere with important signaling pathways involved in growth and proliferation of cells. |
Publications
| Identification of glutathione modifications by cigarette smoke. |
| Periodical: Free Radical Biology and Medicine |
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| Authors: Reddy S, Finkelstein EI, et al |
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| Identification of glutathione modifications by cigarette smoke. |
| Periodical: Free Radical Biology and Medicine |
Index Medicus: |
| Authors: Reddy S, Finkelstein EI, et al |
ART |
| Yr: 0 |
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