Regulations of phase II genes by oxidation products
Initial Award Abstract
Tobacco smoke contains thousands of compounds. Among the most dangerous is a small molecule called acrolein that has been associated with lung damage, lung cancer and cardiovascular disease. Smoking also causes oxidation of the membranes that are critical to the structure of cells and the lung. One of the byproducts from the oxidation of the membranes is called 4-hydroxynonenal, abbreviated as HNE. This compound is also associated with lung damage, cancer and heart disease. The DNA in the lung of smokers has even been shown to be altered by HNE. Nonetheless, an interesting property of acrolein and HNE is that low concentrations of these compounds can cause an increase in several enzymes in the lung that are actually protective against these compounds. These enzymes are responsible the elimination of toxic compounds, such as those in tobacco smoke. They are not only protective against acrolein and HNE but also many other potentially lung and heart damaging and cancer producing compounds in tobacco smoke. Therefore, understanding how these protective enzymes are increased has a potential impact on increasing resistance to the diseases related to tobacco smoking. While the discovery of a harmless substance that induces the protective enzymes that help destroy the toxic compounds in tobacco smoke would be useful, it should be noted that these enzymes do not provide an absolute barrier to injury related to smoking and therefore, does not provide a license for smoking.
The way in which acrolein and HNE increase protective enzymes is not entirely understood in detail but we do know several important facts. In the genes of these protective enzymes is a short section of the DNA that serves as an on-off switch for production of these protective enzymes. The way in which the switch is turned on is through binding of proteins to the DNA. There are small differences in the structures in the switches among the protective enzymes that we propose requires different proteins to bind to the switches both before and after cells are exposed to acrolein or HNE. We also propose that this change in the proteins will alter what must occur within the cell to turn on the various protective enzyme genes. |