Dithranol: Recent views on its mechanism of action

K Pavithran

 Department of Dermato-Venereology, Medical College Hospital, Calicut-673008, India

Correspondence Address:
K Pavithran
Department of Dermato-Venereology, Medical College Hospital, Calicut-673008
India

Dithranol also known as anthralin even after 125 years since its introduction in the treatment of psoriasis still continues to be one of the indispensable topical antipsoriatic agents. The exact mechanism how anthralin exerts its beneficial effect in the treatment of psoriasis is still not well understood. Dithranol in presence of light undergoes autooxidation to produce inactive products, free radicals and reactive oxygen species. Free radical destroys DNA of cells and inactivates enzymes associated with cell proliferation and inflammation. Anthralin doesn′t appear to react with DNA to form adducts that are subject to excision repair.[1]

The central pathogenetic figure in psoriasis is T-lymphocyte which in turn stimulates keratinocyte proliferation and they themselves multiply releasing IL, TNF alpha and IFN gamma. There is upregulation of ICAM and VCAM and migration of leucocytes, monocytes and neutrophils to endothelial cells. Proliferating keratinocytes also release IL, TNF, GF and TGF resulting in inflammation. Dithranol acts on all these steps resulting in inhibition of proliferation of epidermal cells in psoriasis. It has been noted that mononuclear leucocytes are more sensitive than keratinocytes to dithranol-induced lipid peroxidation and INK activation.[2] Recently IL-8 is also assumed to play an important role in pathogenesis of psoriasis. There is an increased expression of IL-8 both in polymorphonuclear leucocytes and in affected psoriatic epidermis. Studies by Kemeny et al revealed that dithranol caused a dose-dependent decrease in IL-8 binding to cultured human keratinocytes.[3]

All the effects exerted by anthralin are caused by its redox activity leading to the generation of anthralin free radicals and oxygen radicals. These species are responsible for antiproliferative and proinflammatory effects of anthralin.[2] In vitro studies have demonstrated that antharlin inhibits human monocytes to secrete IL-6, IL-8 and TNF-alpha, but not IL-1.[4] Reactive oxygen intermediates (ROIS) generated in vivo during autooxidation of anthralin are considered as mediators of inflammatory response. But how this is translated into novel inflammatory gene expression is not yet understood. Studies by Schmidt et al[5] showed that as little as 10 micro M anthralin can activate a prototypic form of transcription factor NF- (Kappa) B, a central transcriptional regulator of inflammation and immune responses. The effects of dithranol on neutrophil superoxide generation in psoriatics have also been studied.[6] Oxidised dithranol had no effect on PMA-stimulated superoxide generation in neutrophil, but when neutrophils were exposed to dithranol before activation, there was a modest dose-related increase in superoxide generation.

Anthralin inhibits leukotriene production and LT B4 - omega oxidation by human neutrophils.[7] But even at high concentrations, dithrone as well as anthralin dimer did not show such an effect.

The down-regulation of epidermal growth factor (EGF) receptor on epidermal cells by dithranol also may contribute to its antipsoriatic action.[8] Dithranol induces a decrease in EGF binding in a dose dependent manner.

The effects of anthralin on human monocyte chemotaxis, superoxide anion generation and enzyme degranulation have been studied. Results showed that it potently inhibited stimulated human monocyte superoxide-anion generation and enzyme degranulation.[9] It has also been demonstrated that anthralin decreased keratinocyte TGF-alpha expression and EGF-receptor binding in vitro.[10]

There is increased lipid peroxidation in the epidermis after dithranol treatment. Malonaldehyde, one of the main products of lipid peroxidation, reacts with epidermal phosphofructokinase and glucose-6-phosphate dehydrogenase to cause enzyme inactivation by cross-linking of the enzyme protein. Enzyme inactivation leads to an inhibition of hexose monophosphate shunt and glycolysis.[11]

It has also been shown that dithranol can down regulate 12 (S) - HETE receptors in human epidermal cell line. This down regulation also contributes to its antipsoriatic effect.[12]

A new mode of action of anthralin has been suggested by Schallreuter and Pittelkow.[13] They measured membrane associated thioredoxin reductase (TR) activity in biopsy specimens from psoriatic and uninvolved skin of patients with chronic plaque type psoriasis vulgaris. Since TR contains 2 reactive thiolate groups at its active site, this enzyme reacts with anthralin to form a covalent anthralin-TR complex causing irreversible enzyme deactivation.[13] This mode of action of anthralin has been confirmed using pure TR from Escherichia coli.

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