9‐ cis retinoic acid is the ALDH 1 A 1 product that stimulates melanogenesis

Aldehyde dehydrogenase 1 A 1 ( ALDH 1 A 1), 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 RNA i and pharmacologic approaches were used to determine which ALDH 1 A 1 substrates and products regulate melanogenesis. Initial studies revealed that neither the UV ‐induced lipid aldehyde 4‐hydroxy‐2‐nonenal nor the ALDH 1 A 1 product all‐ trans retinoic acid appreciably induced melanogenesis. In contrast, both the ALDH 1 A 1 substrate 9‐ cis retinal and its corresponding product 9‐ cis retinoic acid potently induced the accumulation of MITF m RNA , T yrosinase m RNA and melanin. ALDH 1 A 1 depletion inhibited the ability of 9‐ cis retinal but not 9‐ cis retinoic acid to stimulate melanogenesis, indicating that ALDH 1 A 1 regulates melanogenesis by catalysing the conversion of 9‐ cis retinal to 9‐ cis retinoic acid. The addition of potent ALDH 1 A inhibitors (cyanamide or A ngeli's salt) suppressed T yrosinase and MITF m RNA 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.