title: Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin.
abstract: Malassezia yeasts are commensal microorganisms, which under insufficiently understood conditions can become pathogenic. We have previously shown that specific strains isolated from diseased human skin can preferentially produce agonists of the aryl hydrocarbon receptor (AhR), whose activation has been linked to certain skin diseases. Investigation of skin scale extracts from patients with Malassezia-associated diseases demonstrated 10- to 1,000-fold higher AhR-activating capacity than control skin extracts. Liquid chromatography-tandem mass spectrometry analysis of the patients' extracts revealed the presence of indirubin, 6-formylindolo[3,2-b]carbazole (FICZ), indolo[3,2-b]carbazole (ICZ), malassezin, and pityriacitrin. The same compounds were also identified in 9 out of 12 Malassezia species culture extracts tested, connecting their presence in skin scales with this yeast. Studying the activity of the Malassezia culture extracts and pure metabolites in HaCaT cells by reverse transcriptase real-time PCR revealed significant alterations in mRNA levels of the endogenous AhR-responsive genes Cyp1A1, Cyp1B1, and AhRR. Indirubin- and FICZ-activated AhR in HaCaT and human HepG2 cells with significantly higher, yet transient, potency as compared with the prototypical AhR ligand, dioxin. In loco synthesis of these highly potent AhR inducers by Malassezia yeasts could have a significant impact on skin homeostatic mechanisms and disease development.
authors: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Athens, Greece. magiatis@pharm.uoa.gr
authors: Prokopios
authors: P
authors: Magiatis
authors: Periklis
authors: P
authors: Pappas
authors: George
authors: G
authors: Gaitanis
authors: Nikitia
authors: N
authors: Mexia
authors: Eleni
authors: E
authors: Melliou
authors: Maria
authors: M
authors: Galanou
authors: Christophoros
authors: C
authors: Vlachos
authors: Konstantina
authors: K
authors: Stathopoulou
authors: Alexios Leandros
authors: AL
authors: Skaltsounis
authors: Marios
authors: M
authors: Marselos
authors: Aristea
authors: A
authors: Velegraki
authors: Michael S
authors: MS
authors: Denison
authors: Ioannis D
authors: ID
authors: Bassukas
mesh_terms: D006528:Carcinoma, Hepatocellular; D002457:Cell Extracts; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D003881:Dermatomycoses / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000382:microbiology; D008113:Liver Neoplasms; D008290:Malassezia / Q000254:growth & development* / Q000302:isolation & purification / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000382:microbiology*
chemical_list: D002457:Cell Extracts; D007211:Indoles; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C436511:malassezin; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C027185:indirubin