Biochemistry of Antioxidants: Mechanisms and Pharmaceutical Applications

Abstract

Natural antioxidants from fruits and vegetables, meats, eggs and fish protect cells from the damage caused by free radicals. They are widely used to reduce food loss and waste, minimizing lipid oxidation, as well as for their effects on health through pharmaceutical preparations. In fact, the use of natural antioxidants is among the main efforts made to relieve the pressure on natural resources and to move towards more sustainable food and pharmaceutical systems. Alternative food waste management approaches include the valorization of by-products as a source of phenolic compounds for functional food formulations. In this review, we will deal with the chemistry of antioxidants, including their molecular structures and reaction mechanisms. The biochemical aspects will also be reviewed, including the effects of acidity and temperature on their partitioning in binary and multiphasic systems. The poor bioavailability of antioxidants remains a huge constraint for clinical applications, and we will briefly describe some delivery systems that provide for enhanced pharmacological action of antioxidants via drug targeting and increased bioavailability. The pharmacological activity of antioxidants can be improved by designing nanotechnology-based formulations, and recent nanoformulations include nanoparticles, polymeric micelles, liposomes/proliposomes, phytosomes and solid lipid nanoparticles, all showing promising outcomes in improving the efficiency and bioavailability of antioxidants. Finally, an overview of the pharmacological effects, therapeutic properties and future choice of antioxidants will be incorporated.

Keywords: antioxidants; bioactivity; bioavailability; nano antioxidants delivery systems; oxidative stress.

Figure 6

Distribution of reactants between the different regions of a multiphasic system, such as a microemulsion. Φ and k stand for the volume fraction in each particular region and for the second order rate constant for the reaction between A and B in each region, respectively (O–oil, I—interfacial and W—aqueous regions).

Figure 1

Fundamental steps of the lipid autooxidation and inhibition reactions. The main inhibition mechanism comprises the transfer of an H atom from a phenolic antioxidant (ArOH) to the chain carrying a free radical (ROO^•). R-H stands for lipid molecule, and R^•, ROO^• and RO^• are the derived lipoid, peroxyl and alkoxyl radicals, respectively.

Figure 2

Scavenging of ROS. Coordination between various intracellular antioxidant enzymes (SOD, CAT, GR, Gpx) is a crucial mechanism for controlling ROS homeostasis and signaling. Secondary enzymes Gpx and G6PDH sustain the activity of primary enzymes by regenerating NADPH.

Figure 3

General classification of polyphenols.

Figure 4

Proposed mechanisms between antioxidants (ArOH) and peroxyl radicals (ROO^•) comprising the hydrogen atom transfer (HAT), electron transfer–proton transfer (ET-PT) and single-proton-loss electron-transfer (SPLET). S = Solvent. Adapted from reference [6].

Figure 5

Radical scavenging activity of catechol derivatives, where R stands for different substituents.

Figure 7

Chemical structures of the natural CDs showing the spatial conformation, the location of primary and secondary –OH groups and the size of their cavities, and an illustrative representation of an inclusion complex between a gallic acid derivative and cyclodextrins (CDs) [53].

Figure 8

Partitioning of a model phenolic acid antioxidant (caffeic acid) between the oil (O) and water (W) phases of binary mixtures.

Figure 9

(A) Variation with pH of the ratio between the local concentration of the caffeic acid (here represented as AH) in the aqueous region and the total or stoichiometric concentration obtained in corn oil–water systems, T = 25 °C, at two o:w ratios (■—1:9 and ●—1:1, v/v). (B) Effects of acidity on the partition constant P_W^I of caffeic acid in emulsions [58].

Figure 10

An illustrative representation of the distribution of an oil insoluble carboxylic antioxidant (AH) between different regions of an emulsified system. P_W^I and P⁻_W^I stand for the partition constants for the neutral and ionized species of the carboxylic antioxidant.

Figure 11

(A) Different transport pathways across the intestinal cell epithelium. Adapted from [69], Copyright (2022), with permission from Elsevier. (B) General types of membrane transport. (C) Permeability of lipid membranes to different reactive species [60,61,62]. Adapted from reference [60], Copyright (2022), with permission from Elsevier.

Figure 12

Fate of antioxidants in the body and main bioactivities attributed to them.

Figure 13

Schematic presentation of passive drug targeting and enhanced permeability and retention effect (EPR) in tumor tissue. The passive targeting of NDDS to tumors occurs through the spaces between endothelial cells, and a decrease in lymphatic drainage improves this accumulation.

Figure 14

Receptor-mediated active targeting of ligand-modified NDDS. NDDS bind to the relevant specific receptor on the cell surface via the targeting ligands on their structure. NDDS, which undergo receptor-mediated endocytosis after binding, internalize into the cell and release the encapsulated active molecule in the target cell.

Figure 15

Schematic illustration of intestinal NDDS absorption. Transport of free drugs is inhibited via the epithelial cell membrane, viscous mucus layer and intercellular tight junction. Gastrointestinal enzymes and ABC efflux pumps also decrease the intestinal absorption. Possible absorption pathways for NDDS are shown by arrows.

Figure 16

Effects of caffeic acid (CA) on platelet activation in thrombin-simulated platelets (adapted from [148]). Caffeic acid may act as a potential therapeutic compound by inhibiting thrombin-induced platelet aggregation, adenosine 1,4,5-tri-phosphate (ATP) release, the phosphorylations of protein kinase B (AKt) and extracellular signal-regulated kinase (ERK). Moreover, CA may also improve cyclic adenosine monophosphate (cAMP) production, which may induce the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) and inositol trisphosphate (IP3) receptor. Reprinted from [148], Copyright (2022), with permission from Elsevier.