Azelaic acid as a competitive inhibitor of thioredoxin reductase in human melanoma cells.

Azelaic acid has been shown to inhibit thioredoxin reductase (TR) at the surface of guinea pig and human skin, on cultures of human keratinocytes, melanocytes, melanoma cells, murine melanoma cells (Cloudman S91), and on purified enzymes from Escherichia coli, rat liver, and human melanoma. Human melanoma cells are more resistant to inhibition by azelaic acid than murine melanoma or human melanocytes. Kinetic studies with pure TRs indicate that azelaic acid is a reversible competitive inhibitor. Fluorescence spectroscopy has been used to show that azelaic acid does not interfere with electron transfer from NADPH to FAD on TR. However, azelaic acid does inhibit electron transfer from the dithiolate active site of this enzyme. Inhibition by azelaic acid is pH-dependent, requiring the dissociation of both carboxylate groups, and also the dissociation of the active site dithiol groups. Binding studies with [14C]azelaic acid at different pHs, indicate that inhibition is first due to the formation of a thioester on the active thiolate groups followed by transacylation of a basic amino acid residue in the active site. A comparative study of TR inhibition by C6, C9, C10 and C12 saturated dicarboxylic acids was also determined on guinea pig skin in vivo. These homologous dicarboxylic acids gave greater inhibition with increasing size (i.e. mol wt.).