Mechanisms Of Antioxidant Defense By Flavonoids

Three different modes of action are indicated by the available evidence.

1. The mechanism which has been most extensively investigated is metal chelation preventing free radical formation and secondly, the direct scavenging of oxygen and nitrogen free radicals such as hydroxyl, superoxide, and nitric oxide radicals. Most of these studies have been made in vitro or ex vivo systems. Evidence for such activity in body tissues is generally absent or inconclusive.

A pro-oxidant action of quercetin but not of rutin in vitro leading to hydrogen peroxide production has been reported (1). However, the pH dependence of this effect indicates that it is not likely to occur in vivo. The following two mechanisms are likely for many of the protective effects of flavonoids in vivo.

2. A mechanism of great importance in antioxidant defense, detoxification, and cancer prevention is the induction of phase 2 enzymes. Evidence of this important in vivo response to bioflavonoids is from cell, animal, and human studies. Figure 2 illustrates the major pathways of phase 2 enzyme induction. Phase 2 enzyme induction results in synthesis of flavonol and other conjugation enzymes. Major flavonol conjugation enzymes are: Glutathione as in GSH S-tranferases Glucuronic acid as in UDP-glucuronosyltransferases Methylation as with methyl transferases Sulfation as sulfotranferases.

Polyphenols Bioflavonoids Quercetin Curcumin

Hydroperoxides

PHASE 2 Enzyme Induction

Broad range of chemicals reacting with Sulphydryl groups, e.g., Sulforaphane Dithiolanes, ^ 1,2-dithiol-3-thiones

Organic Hydroperoxides

Mn Superoxide |

dismuiase Mitochondrial and Antioxidant enzymes tgcs \

gsh levels increase

_ Alkyl and Aryl Haiides, Metal Ions, e.g., HgCI2, CdCI2

NAP(P}H-Quinone reductase, Ferritin, Epoxide hydrolase GSH, Gluconic acid,methyl and other transferases

Protection against reactive oxygen species and electrophile toxicity ANTIOXIDANT DEFENSE

Figure 2 Phase 2 enzyme induction.

After absorption from the intestine, both Rutin and quercetin are mainly present in vivo in conjugated form. The biological activity of aglycones and conjugated forms is very different. Where studied, free flavo-noids are generally more effective antioxidants and thus more protective than the conjugated form (e.g., quercetin as compared with its conjugate quercetin-3-glucoside) (2).

3. Another mechanism is action by flavonoids is on direct molecular targets with high specificity. These include effects on receptors, enzymes involved in cell signaling (1992), transcription, and gene expression. Some information for selected bioflavonoids has been reported. Animal feeding studies with high-density oligonucleotide arrays (gene chips) demonstrate the presence of target proteins and enzymes (3).

The direct scavenging action against radical flavonols has been extensively studied in in vitro systems which often are not so relevant to their actions in vivo where little is known about the concentration, distribution, and metabolism (4).

Mechanisms 2 and 3 are currently the subject of intense investigation.

All cells possess elaborate antioxidant defense systems that consist of interacting micronutrients, enzymes, and other molecules. Oxidants such as hydroperoxides (H2O2, CH3OOH, ROOH), many natural antioxidant substances, and a broad range of chemicals reacting with sulfydryl groups induce phase 2 enzymes. Phase 2 enzymes protect against oxidants and electrophilic toxicity, i.e., antioxidant defense, detoxification, and cancer prevention. This induction leads to a series of coordinated increases in the gene expression and the enzymatic activity of antioxidant defense system.

Examples of phase 2 enzymes, proteins, and products important in antioxidant defense include glutamate-cysteine ligase, hemeoxygenase-1, Mn superoxide dismutase, NAD(P) H:quinone reductase, dihyrodiol dehydrogenase, exp-oxide hydrolase, leukotiene B4 dehydrogenase, aflatoxin B1

dehydrogenase, and the major intracellular iron binding protein ferritin. Upregulation of these systems result in the protection against reactive oxygen species and electrophile toxicity and therefore are very important in antioxidant defense, detoxification, and cancer prevention.

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