Planta Med 2008; 74 - PB166
DOI: 10.1055/s-0028-1084510

Identification of Indirubin as a metabolite of Malassezia furfur strains isolated from diseased skin

D Giakoumaki 1, K Stathopoulou 1, E Melliou 1, P Magiatis 1, G Gaitanis 2, A Velegraki 3, I Bassukas 2, AL Skaltsounis 1
  • 1Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis-Zografou, Athens 15771, Greece
  • 2Department of Skin and Venereal Diseases, University Hospital of Ioannina, University of Ioannina, Medical School, Ioannina, Greece
  • 3Mycology Laboratory, Department of Microbiology, Medical School, University of Athens, Athens, Greece

Seborrheic dermatitis (SD), pityriasis versicolor (PV) and dandruff (DF) are common skin diseases that are unequivocally associated with Malassezia yeasts. In a previous work [1] we compared M. furfur isolates from healthy and SD skin for the production of indole derivatives, using HPLC-UV and identified the preferential biosynthesis of several known indole derivatives [2,3] such as malassezin, pityriacitrin, malassezindol A, indol-3-carboxaldehyde, indolo[3,2-b]carbazol (ICZ) by M. furfur strains isolated from diseased skin. Further investigation of ethyl acetate extracts of M. furfur strains grown on L-tryptophan agar originating from SD, PV and DF, using preparative HPLC, led to -in addition to the aforementioned indoles- the isolation and structure elucidation by NMR and MS of indirubin. Indirubin which is a known highly potent ligand of the Aryl hydrocarbon receptor (AhR) and a strong inhibitor of several protein kinases is described for the first time as a metabolite of M.furfur. Isolated indirubin was used as standard for the development of an analytic methodology using HPLC-DAD. HPLC analysis of the extracts coming from 15 reference and clinical strains (7 healthy, 8 disease) revealed the preferential in vitro production of indirubin only by M. furfur strains isolated from skin lesions and not healthy skin controls. The selective production of compounds like ICZ and indirubin which are active AhR ligands offers indirect, statistical significant evidence in favor of the variable pathogenic potential within M. furfur strains as well as the possible implication of AhR activation in the pathogenesis of PV, SD and DF. In addition, the common facial distribution of SD and basal cell carcinoma, coupled by the inhibitory effect of indirubin on the GSK-3 enzyme – a Hedgehog pathway implicated enzyme – are suggestive of the potential implication of Malassezia metabolites in the development of non-melanoma skin cancer.

Indirubin

References: 1. Gaitanis, G. et al. (2008)J Invest Dermatol 128: 1620–1625 2. Wille, G. et al. (2002) Bioorg. Med. Chem 9: 955–960 3. Krämer, H.J. et al. (2005) ChemBioChem 6: 860–865.