A new mechanism of action for skin whitening agents: binding to the peroxisome proliferator‐activated receptor¹

<jats:title>Synopsis</jats:title><jats:p>Octadecenedioic acid is known as a skin whitening agent but its activity is not mediated via a direct inhibition of tyrosinase. Based on the secondary properties of this molecule, such as its anti‐inflammatory and anti‐ageing effects, we postulated that octadecenedioic acid interacted with the peroxisome proliferator‐activated receptor (PPAR) as this nuclear receptor also mediates these effects. Using reporter gene technology, we were indeed able to demonstrate binding of octadecenedioic acid to all three PPAR subtypes, in particular PPAR<jats:italic>γ</jats:italic> with an EC<jats:sub>50</jats:sub>‐value of approx. 1 × 10<jats:sup>−6</jats:sup> <jats:sc>m</jats:sc>. Binding to PPAR<jats:italic>γ</jats:italic> of octadecenedioic acid or rosiglitazone, a known pharmaceutical PPAR<jats:italic>γ</jats:italic> agonist, led to reduced melanogenesis. Subsequently also tyrosinase mRNA (as measured by real‐time polymerase chain reaction) and tyrosinase levels (as measured by Western blot) were reduced, suggesting the existence of a complete novel mechanism of skin whitening agents: binding to PPAR<jats:italic>γ</jats:italic> results in reduced tyrosinase mRNA expression which in turn results in less tyrosinase being formed. This in turn leads to reduced melanogenesis both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> Because octadecenedioic acid binds not only to PPAR<jats:italic>γ</jats:italic> but also to PPAR<jats:italic>α</jats:italic> and PPAR<jats:italic>δ</jats:italic>, other efficacies mediated via these receptors may also be expected.</jats:p>