The Role of Glutathione-S Transferase in Psoriasis and Associated Comorbidities and the Effect of Dimethyl Fumarate in This Pathway

Abstract

Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated scaly plaques. Oxidative stress plays a crucial role in the psoriasis pathogenesis and is associated with the disease severity. Dimethyl fumarate modulates the activity of the pro-inflammatory transcription factors. This is responsible for the downregulation of inflammatory cytokines and an overall shift from a pro-inflammatory to an anti-inflammatory/regulatory response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. Several studies reported a long-term effectiveness and safety of dimethyl fumarate monotherapy in patients with moderate-to-severe psoriasis. Furthermore, psoriasis is a chronic disease often associated to metabolic comorbidities, as obesity, diabetes, and cardiovascular diseases, in which glutathione-S transferase deregulation is present. Glutathione-S transferase is involved in the antioxidant system. An increase of its activity in psoriatic epidermis in comparison with the uninvolved and normal epidermal biopsies has been reported. Dimethyl fumarate depletes glutathione-S transferase by formation of covalently linked conjugates. This review investigates the anti-inflammatory role of dimethyl fumarate in oxidative stress and its effect by reducing oxidative stress. The glutathione-S transferase regulation is helpful in treating psoriasis, with an anti-inflammatory effect on the keratinocytes hyperproliferation, and in modulation of metabolic comorbidities.

Keywords: comorbidities; dimethyl fumarate; glutathione-S-transferase; pathway; psoriasis.

Figure 1

Effects of DMF on intracellular signaling pathways. Upon ingestion, most of the DMF (about 90%) is rapidly converted to MMF by hydrolization in the small intestine (5). The full pharmacokinetic profile of DMF and MMF remains to be elucidated. DMF, dimethyl fumarate; MMF, monomethil fumarate; FAEs, fumaric acid esters; GP, glutathione peroxidase; GST, glutathione-S transferase; NF-kappaB, nuclear factor-kappa B; Nrf2, nuclear factor (erythroid-derived 2)-like 2; ROS, reactive oxygen species; and TCA, tricarboxylic acid cycle.