Addressing Free Radical Oxidation in Acne Vulgaris.

Acne vulgaris is the most common dermatologic condition in the United States and is a condition that has a multifactorial pathogenesis and an etiology that currently remains unknown.1,2 Traditionally, it has been characterized by excessive sebum production, follicular epithelial hyperkeratosis, and rupture of follicular epithelium, resulting in an increased release of inflammatory mediating agents. Bacterial colonization (Propionibacterium acnes) has also been implicated in the pathology.3,4 The above characterizing features of acne vulgaris represent deviations in processes that normally take place within the pilosebaceous units of healthy skin. Previous studies have reported that oxidative stress components, such as reactive oxygen species (ROS) and lipid peroxide (LPO), may be involved in parts of the pathogenesis and progression of acne vulgaris.2,5,7-11 During the formation of a ROS, oxygen will acquire an unpaired electron, thus forming a free radical. This free radical then has the ability to produce other ROS, such as peroxides, resulting in oxidative damage that may include lipid peroxidation and the secretion of inflammatory cytokines. The skin is especially susceptible to resultant oxidative damage, as it is chronically exposed to ROS-induced oxidative stress that is generated both from endogenous and exogenous sources. Endogenous sources of ROS in the skin include auto-oxidation and enzymatic oxidation. Auto-oxidation involves a three-stage process: First, a free radical initiates the ultimate production of ROS, by extracting a hydrogen atom from a methylene group of polyunsaturated fatty acids.5 This is known as the initiation stage. The propagation stage then occurs, in which the fatty-acid-lipid-peroxyl radical is able to extract hydrogen from another lipid molecule, particularly in the presence of heavy metals (i.e., zinc, copper, etc.), thus causing an autocatalytic chain reaction. The catalytic chain reaction is interrupted during the third stage, called termination, in which the lipid-peroxyl radical is reduced to a stable lipid peroxide. This is achieved via an antioxidant, such as alpha-tocopherol, in the skin’s microenvironment.5 The other endogenous process through which lipid peroxides can form is via enzymatic oxidation. During enzymatic oxidation, lipoxygenase catalyzes the oxidation of polyunsaturated fatty acids, such as linoleic and arachidonic acids. Cycloperoxidases then catalyze polyunsaturated fatty acids and oxygen into endoperoxides, which are intermediates formed prior to conversion into prostaglandins. All enzymatic-produced free radicals are biologically active, thus an increased activity of the enzymatic oxidation process may result in an accumulation of ROS in the pilosebaceous units. This likely contributes to the abnormalities associated with acne vulgaris.5-7,13 Excessive ROS may also be generated as byproducts of enzymatic peroxidation related to bacterial enzymes and the action of neutrophils and other immune response mechanisms triggered by the events occurring within the pilosebaceous unit.5,9,12 In addition to endogenous sources, photooxidation and pollutant/environmental oxidants also contribute to the pathogenesis of acne via the production of ROS. All unsaturated lipids are suspect to photooxidation in the presence of sensitizers, such as ultraviolet (UV) light. During photooxidation, a singlet oxygen (photooxidant type 2, or PO2) employs a direct attack by the electrophilic oxygen on the lipid chain at the site of the double bond.5,10,12-13 This allows for the extraction of a hydrogen bond from a CH-group, rapidly initiating the propagation of molecule-to-molecule peroxidation. Both singlet (PO2) and triplet oxygen (PO1) species are generated by exposure to UV light, toxic molecules, and/or environmental factors. However, the PO2, or singlet oxygen, predominates. The generation of ROS then proceeds in a manner similar to auto-oxidation as explained above. The production of ROS, as initiated by free radicals during photooxidation is 1,000 to 1,500 times faster than auto-oxidation, as the former does not require an initiation step.5,10,12-13 The involvement of free radical oxidation (FRO) in each of the major abnormalities associated with acne has been suggested, as ROS and lipid peroxidation may play a role in the initiation and progression of epithelial inflammation in the pilosebaceous unit.2,5,7-10 In acne, sebum composition is altered. Lipid peroxidation of fatty acids and unsaturated triterpenes, such as squalene, generates both intracellular and extracellular ROS. The generation of ROS can alter the viscosity and composition of sebum.5,14 In fact, the excessive sebum production in acne is expected to promote the generation of excess ROS, leading to oxidative stress within the follicle, thus overwhelming the antioxidant system of the skin.5,14 The oxidants generated by lipid peroxidation are also suspected of promoting the formation of hyperkeratinous impactions. These powerful oxidants are capable of comedogenic potentiation.5-6,14 Lipid peroxides can lead to the formation of advanced glycation end products (AGEs) via formation of byproducts, such as malondialdehyde (MDA), which can cross-link with proteins and alter the rigidity of keratin, thus enhancing follicular impaction. Could FRO also dictate the rate of appearance of acne lesions? Perhaps amino acid residues containing disulfides (cysteine) in peptide chains are more susceptible to cross-linking and plug formation. This is sporadic, but is certainly suggestive of a potentially continuous cycle, which exacerbates the clinical appearance of acne lesions. Additionally, lipid peroxides can induce inflammatory responses in the follicles’ walls, ultimately weakening the walls and making them more susceptible to rupture. ROS produced by neutrophils are also implicated in the irritation and destruction of the follicular wall. As a result of the destruction of the follicle wall, follicular contents are released into the surrounding tissue, resulting in a foreign body reaction.13 Oxidative stress in lipid peroxidation may also be an initiator for the release of inflammatory agents that contribute to the initiation of pathology.6,7 Elevated pro-inflammatory factors, such as interleukin-1 (IL-1), have been noted to appear around clinically normal pilosebaceous follicles of acne patients prior to hyperproliferative and abnormal differentiation events.7,8 Under normal conditions, the antioxidant defense system of the skin prevents the formation of free radicals and ROS in pilosebaceous units, thus preventing oxidative injury of the structural lipids and proteins that maintain the integrity of the skin.13 Non-enzymatic antioxidants, such as alpha-tocopherol (vitamin E) and beta-carotene, interact with free radicals, such as lipid peroxyl radicals, to prevent lipid peroxidation in the skin’s microenvironment. However, in the presence of excessive lipid peroxidation and excess ROS, the redox balance (loss or gain of electrons) of the skin is offset, leading to a reduction in protective antioxidants, such as vitamin E. Vitamin E is a lipid soluble antioxidant that neutralizes the oxidant effect of free radicals and thus prevents cellular damage.15 High levels of vitamin E are found in sebum and sebum-rich areas, such as the upper layers of facial skin.16,17 The sebaceous gland delivery of vitamin E may serve to protect the skin surface from oxidation, which may ultimately lead to the lipid peroxidation. However, when excess sebum is produced, the endogenous vitamin E supply may be overwhelmed, resulting in a reduction of this antioxidant and an increase in oxidative stress. The influence of a high oxidative load on an overwhelmed antioxidant defense system is implicated in the pathogenesis of acne vulgaris. Studies have indicated that daily oral supplementation of alpha-tocopherol leads to significant increases of vitamin E levels in the human skin, most notably at sites with a high density of sebaceous glands.16 Additionally, research has indicated that serum vitamin E levels negatively correlate with the severity of acne vulgaris in patients.18 Results from a UV erythema study demonstrated that pre-treatment of skin with topical alpha-tocopherol reduced UV-induced skin erythema in those with skin type II.19 These results are attributed to vitamin E’s antioxidant potential, in which the ROS that give rise to the post-UV-induced erythemal response were mitigated by the presence of vitamin E. Thus, the addition of vitamin E to current treatments for acne vulgaris may reduce the oxidative stress in the pilosebaceous unit and thus, decrease the ROS associated with acne vulgaris. Since oral vitamin E can take weeks before affecting sebum, supplementation with topical vitamin E is often more appealing for treatment. The growing antibiotic resistance of P. acnes to systemic and topical antibiotics20 has motivated dermatologists to look for alternative treatment options that decrease reliance on antibiotics, most notably benzoyl peroxide (BPO). Although undoubtedly beneficial, the use of BPO has also been demonstrated to reduce endogenous epidermal vitamin E by up to 95 percent, which is of much concern since the major route of delivery of vitamin E is via sebaceous glands. The supplementation of BPO with topical vitamin E has been suggested. Previous studies have indicated that the presence of vitamin E and other tertiary amines enhances the efficacy and tolerability of topical BPO.21,22 Furthermore, it has been found that applying vitamin E in advance of BPO may lead to enhanced effects in the treatment of acne vulgaris, although more research is necessary.22