Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin

Figure 6

Possible pathways involving TPA induced generation of ROS and promising targets of NDGA. (1) NDGA prevents the TPA induced dermal infiltration and activation of PMNs. (2) NDGA downregulates MPO, one of the principal enzymes released upon PMN activation. MPO has been considered a key constituent of the PMNs cytotoxic armament by catalyzing the H₂O₂ dependent formation of HOCL, a potent oxidant. (3) It inhibits the activity of XO and thus prevents the formation of O₂^•−. This O₂^•− is a substrate for the enzyme SOD, which catalyzes the formation of H₂O₂. H₂O₂ may be converted into highly reactive radical OH^•. This OH^• may interact with lipid-rich plasma membrane and DNA molecule causes LPO and DNA damage that may result into tumor development. (4) NDGA may quench the hydroxyl radicals and thus prevents from deleterious effects. (5) NDGA also inhibits LPO. Confirmed (1–3 and 5) and unconfirmed intervention (4) are shown by unbroken and broken lines, respectively. TPA, 12-O-tetradecanoylphorbol-13-acetate; ROS, reactive oxygen species; NDGA, nordihydroguaiaretic acid; PMNs, polymorphonuclear leukocytes; MPO, myeloperoxidase; H₂O₂, hydrogen peroxide; HOCL, hypochlorous acid; XO, xanthine oxidase; SOD, superoxide dismutse; OH^•, hydroxyl radical; LPO, lipid peroxidation.