title: 9-cis retinoic acid is the ALDH1A1 product that stimulates melanogenesis.
abstract: Aldehyde dehydrogenase 1A1 (ALDH1A1), an enzyme that catalyses the conversion of lipid aldehydes to lipid carboxylic acids, plays pleiotropic roles in UV-radiation resistance, melanogenesis and stem cell maintenance. In this study, a combination of RNAi and pharmacologic approaches were used to determine which ALDH1A1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV-induced lipid aldehyde 4-hydroxy-2-nonenal nor the ALDH1A1 product all-trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH1A1 substrate 9-cis retinal and its corresponding product 9-cis retinoic acid potently induced the accumulation of MITF mRNA, Tyrosinase mRNA and melanin. ALDH1A1 depletion inhibited the ability of 9-cis retinal but not 9-cis retinoic acid to stimulate melanogenesis, indicating that ALDH1A1 regulates melanogenesis by catalysing the conversion of 9-cis retinal to 9-cis retinoic acid. The addition of potent ALDH1A inhibitors (cyanamide or Angeli's salt) suppressed Tyrosinase and MITF mRNA accumulation in vitro and also melanin accumulation in skin equivalents, suggesting that 9-cis retinoids regulate melanogenesis in the intact epidermis. Taken together, these studies not only identify cyanamide as a potential novel treatment for hyperpigmentary disorders, but also identify 9-cis retinoic acid as a pigment stimulatory agent that may have clinical utility in the treatment of hypopigmentary disorders, such as vitiligo.
authors.affiliation: Department of Biological Chemistry, University of California, Irvine, CA 92697-2400, USA.
authors.forename: Elyse K
authors.initials: EK
authors.lastname: Paterson
authors.forename: Hsiang
authors.initials: H
authors.lastname: Ho
authors.forename: Rubina
authors.initials: R
authors.lastname: Kapadia
authors.forename: Anand K
authors.initials: AK
authors.lastname: Ganesan
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000077556:Alitretinoin; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003484:Cyanamide / Q000494:pharmacology; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D050697:Retinal Dehydrogenase; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D012880:Skin Pigmentation / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D000077556:Alitretinoin; D003484:Cyanamide; D014212:Tretinoin; D014442:Monophenol Monooxygenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase