Naturally occurring polyphenols – Mechanisms of Drug Action and Side Effects

Naturally occurring polyphenols exhibit various activities including antioxidant, hormonal, neuronal and antimicrobial activity. Due to such diverse activities, the mechanisms of action differ widely.

Mechanism of Antioxidant Activity

The principal mechanism accounting for antioxidant properties of polyphenols is their scavenger capacity for free radicals and other reactive species. Polyphenols occur in highly reduced forms that can serve to donate an electron or hydrogen atom to electron deficient species (e.g. peroxides) generated in the course of metabolism (Heim et al. 572-582; Handique and Baruah 180-182; Tsao 1242). In such a way, the polyphenols deactivate the reactive species thus preventing such species from reacting with and causing damage to cellular components (See reaction below). After donating their electrons or hydrogen atoms, the polyphenols still remain as relatively stable radicals thus stopping a chain of reactions that could result into cell damage (Heim et al. 572-582; Handique and Baruah 180-182; Tsao 1242).

Figure 2: Reaction between hydroxyl groups of a flavonoid and a free radical to form a stable flavonoid radical

radical

Source: Heim, Kelly E., Anthony R. Tagliaferro and Dennis J. Bobilya. “Flavonoid Antioxidants: Chemistry, Metabolism and Structure-Activity Relationships.” The Journal of Nutritional Biochemistry 13.10 (2002): 576. ScienceDirect. Web. 16 December 2011.

Apart from direct inactivation of reactive species and halting the sequence of reactions that would arise in their absence, polyphenols also can prevent oxidation by chelating metal facilitators of such oxidation (Heim et al. 572-582; Handique and Baruah 180-182; Tsao 1242). Transitional metals such as Fe 2+ are susceptible to oxidation by highly reactive OH radicals to Fe3+ thus disrupting cellular components reliant on the integrity of the reduced (ferrous) iron cation (Tsao 1242). Other antioxidant benefits of polyphenols have been noted with respect to neuroprotection. For instance, Campos-Esparza et al. have demonstrated that mangiferin and morin provide protective functions to neurons by reducing “the formation of reactive oxygen species, activat[ing] the enzymatic antioxidant system and restor[ing] the mitochondrial membrane potential” (358). Such neuroprotective effects have been replicated with other polyphenols (e.g. see fig 3 in the appendix, Braidy, et al. 377). Some polyphenols (e.g. myricetin and baicelein) however exhibit prooxidant activity responsible for cytotoxic and proapoptotic effects noted in extracts from various herbal medications (Heim 580-581; Rietjens et al. 326-330). However, it remains unclear whether polyphenols maintain such prooxidant activity in vivo (Tsao 1242).

Mechanisms of Antibacterial Activity

Antibacterial activity of polyphenols is thought to proceed via disruption of bacterial topoisomerase activity (Mukne et al. 17). Two types of type II topoisomerase (topo IV and DNA Gyrase) have been identified in bacteria (Mukne et al. 17). Topo IV facilitates the separation of bacterial DNA by breaking the covalent linkages joining the double-stranded bacterial DNA (Mukne et al. 17). DNA gyrase either introduces negative supercoils into DNA or relaxes positive supercoils thus allowing bacterial DNA to have free negative supercoils while retaining the replication ability (Mukne et al. 17). The inhibition activity of isoflavones is principally on topo IV by stabilizing the topo II-DNA intermediate thus preventing further reaction necessary to allow replication (Mukne et al. 17). Such activity is for instance evident in genistein, which inhibits topo-IV activity rather than DNA-gyrase activity, thus having beneficial effects on S. aureus infections but no beneficial outcomes on E. coli infections where DNA gyrase is the targeted enzyme (Mukne et al. 17).

Other Mechanisms of Polyphenols Beneficial Health Outcomes

Other beneficial health outcomes of polyphenols arise from inhibition of fat metabolism enzymes, enhancing susceptibility of cancerous cells to therapeutic approaches and enhancing efficacy of hormone replacement therapy. Some polyphenols (e.g. luteolin and kaempferol), inhibit Fatty acid synthase thus bearing positive outcomes on disorders such as obesity that arise from accumulation of fats (Li, Ma, Wang and Tian 679-685). In cancer treatment, polyphenols are argued to increase sensitivity of cancerous cells to TNF-related apoptosis-inducing ligand (TRAIL) thus overcome the resistance of such cells to therapeutic approaches targeting TRAIL and its receptors (Jacquemin, Shirley and Micheu 3115). In hormone replacement therapy, structural similarities between isoflavones and estrogen allow isoflavones to bind to estrogen receptors that are involved in the regulation of DNA transcription (Albulescu and Popovici 546-547). The estrogen-like effects of isoflavones are limited in perimenopausal women and become more pronounced in postmenopausal women, indicating that endogenous estrogen levels influence the activity of isoflavones (Albulescu and Popovici 546-547). Go to the conclusion here.

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