A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis

Abstract

Fumaric acid esters (FAEs) such as dimethylfumarate (DMF) are used for the treatment of adults with moderate-to-severe psoriasis. The mode of action of FAEs is complex. Here, we provide a comprehensive review of the literature to describe the molecular mechanisms by which DMF and its active metabolite monomethylfumarate (MMF) exert their anti-inflammatory and immune modulatory effects. MMF can bind to the hydroxy-carboxylic acid receptor 2 (HCA2) on the cell surface and both DMF and MMF react with intracellular glutathione following cell penetration. DMF and to some extent also MMF modulate the activity of certain cellular signalling proteins such as the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor kappa B (Nf-κB) and the cellular concentration of cyclic adenosine monophosphate. Some studies show that DMF can also affect the hypoxia-inducible factor 1-alpha (HIF-1α). These actions seem to be responsible for i) the downregulation of inflammatory cytokines and ii) an overall shift from a proinflammatory Th1/Th17 response to an anti-inflammatory/regulatory Th2 response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. There is a growing body of evidence to support the notion that DMF/MMF may also exert effects on granulocytes and non-immune cell lineages including keratinocytes and endothelial cells. A better understanding of the multiple molecular mechanisms involved in the cellular action of FAEs will help to adapt and further improve the use of such small molecules for the treatment of psoriasis and other chronic inflammatory diseases.

No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P‐glycoprotein (P‐gp) drug transporter

“…This initiates a downstream cellular response to oxidative stress and shifts the immune response from a proinflammatory T helper 1/T helper 17 cell profile to an anti-inflammatory Th2 profile. 1 The mechanism of action of DMF may also involve the inhibition of ribosomal S6 kinases and mitogen-and stress-activated kinases, primarily via allosteric covalent binding to a conserved cysteine residue. 6 Many drugs act as inhibitors of cytochrome P450 (CYP) enzymes in vivo and thus may affect the disposition of other coadministered drugs that are also metabolized by these enzymes.…”

Analyzing Cysteine Site Neighbors in Proteins to Reveal Dimethyl Fumarate Targets

“…Monomethyl fumarate (MMF) and fumarate, which are formed from DMF via hydrolysis, have been shown to mimic responses to their parent compound both in vitro and in vivo, and thus these compounds may contribute together to the effects of the DMF‐based drug products. In addition, the pharmacological activity of these related compounds has been associated, at least in part, to their reactivity toward the thiol group in the side chain of certain cysteine residues in proteins . In fact, cell exposure to DMF has been shown to increase the abundance of cysteine residues modified by DMF and/or its metabolites .…”

“…Dimethyl fumarate is converted into a set of metabolites following oral administration. [5] Monomethyl fumarate (MMF) and fumarate, which are formed from DMF via hydrolysis, have been shown to mimic responses to their parent compound both in vitro and in vivo, [3][4][5][6][7][8][9][10][11] and thus these compounds may contribute together to the effects of the DMF-based drug products. In addition, the pharmacological activity of these related compounds has been associated, at least in part, to their reactivity toward the thiol group in the side chain of certain cysteine residues in proteins.…”

“…In addition, the pharmacological activity of these related compounds has been associated, at least in part, to their reactivity toward the thiol group in the side chain of certain cysteine residues in proteins. [10,11] In fact, cell exposure to DMF has been shown to increase the abundance of cysteine residues modified by DMF and/or its metabolites. [7,8,12,13] However, only few of these modifications have been clearly related to the effects of the DMF-based drugs thus far.…”

“…In contrast, some errors were detected when LDA and CIT were tested. [2][3][4][5][6][7][8][9][10][11][12] 6 [3][4][5][6][7][8][9][10][11][12] NMC, median [range] 7 [3][4][5][6][7][8][9][10][11][12][13][14] 8 [2][3][4][5][6][7][8][9][10][11][12][13] RIN, residue interaction network; MC, modifiable cysteine; NMC, non-modifiable cysteine.…”