Page 332 - Industrial Ventilation Design Guidebook

288 CHAPTER 5 PHYSIOLOGICAL AND TOX1COLOGICAL CONSIDERATIONS

electron. These are extremely reactive, and readily react with cellular lipids,
causing lipid peroxidation, where polyunsaturated fatty acids are converted
to Hpid peroxyradicals that are further changed to lipid hydroxy-peroxides.
These are then the source for lipid peroxides. This is a typical chain reac-
tion that continues until it is stopped by antioxidants. 128 If there is a short-
age of antioxidants in the cell e.g., due to oxidative stress that has depleted
GSH, the end result may be cell death. Thus, intracellular thiols, especially
glutathione, are extremely important in preventing radical-induced cellular
injuries. 128 Figure 5.47 depicts the role of glutathione in the protection of
cells against attack by electrophiles, oxidants, and reactive oxygen spe-
cies. 64
Nucleic acids in the DNA contain a high number of nucleophilic sites that
can be attacked by electrophilic intermediates (metabolites) of chemical com-
pounds. DNA adducts formed may cause alterations in the expression of a
critical gene in the cell and thus lead to cell death. For example, modification
of p53 tumor suppressor gene may inactivate the functions of the p53 protein
and render cells sensitive to malignant transformation. Also, formation of
RNA adducts may inhibit key cellular events because RNA is essential for pro-
tein synthesis.

FIGURE 5.47 The role of glutathione and metabolic pathways involved in the protection of tissues
65
against intoxication by electrophiles, oxidants and active oxygen species. (Used with permission.)