carnosol and fisetin

Oxidative stress is implicated in the etiology of cancer, hence compounds that alleviate oxidative stress by inducing enzymes that defend against free radical damage might be useful as cancer chemopreventives. Glutathione S-transferase (GST) has been suggested to be a candidate for a critical enzyme in protecting cells against free radical damage, in part, because its level of induction correlates with protection of the cell line IMR-32 against hydrogen peroxide-induced oxidative stress. The present study identified dietary ortho phenols that both induce GST and protect the cell line IMR-32 against hydrogen peroxide-caused oxidative stress. The ortho phenol (o-phenol) inducers were better protectors against oxidative stress than a number of GST inducers that did not bear phenolic groups, possibly because the phenol residues of the ortho phenols allowed their action as antioxidants as well as inducers of GST. GST has previously been thought to protect cells against cancer by detoxifying mutagenic xenobiotics. The present results suggest that ortho phenol inducers of GST might be useful as cancer chemopreventives that act by two independent mechanisms, the alleviation of oxidative stress and the detoxification of mutagenic xenobiotics.

Topics: Abietanes; Anticarcinogenic Agents; Antioxidants; Diet; Diterpenes; Enzyme Induction; Flavonoids; Flavonols; Glutathione Transferase; Humans; Hydrogen Peroxide; Inactivation, Metabolic; Inhibitory Concentration 50; Isomerism; Mutagens; Oxidative Stress; Phenanthrenes; Phenols; Plant Extracts; Structure-Activity Relationship; Tumor Cells, Cultured

We investigated the ability of various plant flavonoids (a) to inhibit 5-lipoxygenase and cyclooxygenase activities in rat peritoneal leukocytes, (b) to inhibit lipid peroxidation in rat liver microsomes, and (c) to stimulate DNA degradation caused by the antibiotic bleomycin in the presence of ferric ions. These compounds were compared with a range of synthetic phenolic substances including carnosol, vanillin, vitamin E and its analogue trolox c. The flavonoids were potent inhibitors of non-enzymatic peroxidation in membranes but this was not significantly correlated with their ability to inhibit either pathway of eicosanoid synthesis, suggesting that their mode of inhibition of 5-lipoxygenase/cyclooxygenase is not simply due to interception of peroxyl radicals generated at the active site of the enzymes. Many of the flavonoids and other compounds (including carnosol, vitamin E and trolox c) stimulated Fe3+/bleomycin-dependent DNA degradation. Those flavonoids which stimulated DNA degradation at low concentrations but which inhibited it at higher concentrations ("biphasic" effect, possibly caused by changing relative contributions of ability to reduce ferric-bleomycin or to chelate iron ions from the bleomycin) were selective inhibitors of 5-lipoxygenase compared to cyclo-oxygenase. In contrast, those flavonoids that did not stimulate DNA degradation at all proved to be cyclo-oxygenase selective inhibitors. Compounds that increased Fe3+/bleomycin-dependent DNA damage up to a maintained plateau were non-selective inhibitors of both 5-lipoxygenase and cyclo-oxygenase. Thus, a combination of iron-chelating and iron ion-reducing properties appears to be required for selective 5-lipoxygenase inhibition by phenolic compounds. Carnosol, vitamin E and trolox c were also found to be 5-lipoxygenase inhibitors of varying potency, and all were less active as cyclo-oxygenase inhibitors.

Topics: Abietanes; Animals; Antioxidants; Ascorbic Acid; Chromans; Cytochrome c Group; Diet; DNA Damage; Female; Ferric Compounds; Flavonoids; Flavonols; Leukocytes; Lipid Peroxidation; Lipoxygenase Inhibitors; Microsomes, Liver; Oxidation-Reduction; Oxygenases; Phenanthrenes; Phenols; Plant Extracts; Quercetin; Rats; Rats, Inbred Strains; Vitamin E