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Increase of intracellular methylglyoxal levels as a mode of action of retinoids against psoriasis

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Increase of intracellular methylglyoxal levels as a mode of action of retinoids against psoriasis
MR Namazi MD
Dermatology Online Journal 13 (2): 30

Dermatology Department and Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. namazi_mr@yahoo.com

Oral synthetic retinoids have been established as effective systemic therapy for psoriasis since their introduction for clinical use in the 1970s. Despite the demonstrated clinical success of retinoid therapy in psoriasis and other proliferative skin disorders, their mechanism of action has not been fully elucidated. Altered vitamin A metabolism, characterized by an increase in the formation of retinoic acid, has been demonstrated in psoriatic lesions and is potentially influenced by cytokines such as interferon gamma, which is present in high levels in these lesions. Synthetic retinoids such as acitretin may interfere with such cytokine-induced alterations [1]. Retinoids down-regulate the expression of metalloproteinases, cytokines, and other genes involved in cell proliferation and inflammation [2]. Inhibition of epidermal ornithine decarboxylase activity, being elevated in psoriasis, may represent another mechanism of retinoid action on the psoriatic skin [3]. Below, I suggest that elevation of intracellular methylglyoxal levels may play an important role in this therapeutic efficacy:

Methylglyoxal is a substance which is produced by rapidly proliferating cells and exerts a suppressive effect on the cellular proliferation [4]. Methylglyoxal is removed through conjugation with glutathione, performed by the enzymatic action of glutathione-s-transferase [4]. Retinoids are shown to behave as efficacious uncompetitive inhibitors of mammalian glutathione-s-transferase [5]. Therefore, retinoids may owe a part of their therapeutic action against psoriasis to the elevation of methylglyoxal levels as the result of glutathione-s-transferase inhibition. This mechanism could also explain the efficacy of theses agents against some tumors.

References

1. Saurat J-H. Retinoids and psoriasis: novel issues in retinoid pharmacology and implications for psoriasis treatment. J Am Acad Dermatol. 1999;41(3 Pt 2):S2-6.

2. Nagpal S, Thacher SM, Patel S, Friant S, Malhotra M, Shafer J, et al. Negative regulation of two hyperproliferative keratinocyte differentiation markers by a retinoic acid receptor-specific retinoid: insight into the mechanism of retinoid action in psoriasis. Cell Growth Differ. 1996;7(12):1783-91.

3. Lowe NJ, Kaplan R, Breeding J. Etretinate treatment for psoriasis inhibits epidermal ornithine decarboxylase. J Am Acad Dermatol. 1982;6(4 Pt 2 Suppl):697-8.

4. Yildiz D. Inhibition of tumor growth by replacing glutathione with N-acetyl-L-cysteine. Med Hypotheses. 2004;63(1):80-2.

5. Kasraee B, Handjani F, Aslani FS. Enhancement of the depigmenting effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection? Dermatology. 2003;206(4):289-91.

© 2007 Dermatology Online Journal