title: 4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation.
abstract: BACKGROUND
  Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern. Therefore, many topical products are available, containing various active ingredients aiming to reduce melanin production and distribution. The most prominent target for inhibitors of hyperpigmentation is tyrosinase, the key regulator of melanin production. Many inhibitors of tyrosinase are described in the literature; however, most of them lack clinical efficacy.
  
  
  METHODS
  We were interested in evaluating the inhibition of skin pigmentation by well-known compounds with skin-whitening activity like hydroquinone, arbutin, kojic acid and 4-n-butylresorcinol. We compared the inhibition of human tyrosinase activity in a biochemical assay as well as inhibition of melanin production in MelanoDerm skin model culture. For some compounds, the in vivo efficacy was tested in clinical studies.
  
  
  RESULTS
  Arbutin and hydroquinone only weakly inhibit human tyrosinase with a half maximal inhibitory concentration (IC(50)) in the millimolar range. Kojic acid is 10 times more potent with an IC(50) of approximately 500 μmol/L. However, by far the most potent inhibitor of human tyrosinase is 4-n-butylresorcinol with an IC(50) of 21 μmol/L. In artificial skin models, arbutin was least active with an IC(50) for inhibition of melanin production > 5000 μmol/L. Kojic acid inhibited with an IC(50) > 400 μmol/L. Interestingly, hydroquinone inhibited melanin production in MelanoDerms with an IC(50) below 40 μmol/L, probably due to a mechanism different from tyrosinase inhibition. Again, 4-n-butylresorcinol was the most potent inhibitor with an IC(50) of 13.5 μmol/L. In vivo efficacy of 4-n-butyl-resorcinol was confirmed in clinical studies. Subjects with age spots on the forearm treated twice daily two age spots with a formula containing 4-n-butylresorcinol and two control age spots with the corresponding vehicle. Within 8 weeks, 4-n-butylresorcinol reduced visibly the appearance of age spots, while the control spots showed no improvement. A second study showed that 4-butylresorcinol was more effective than 4-hexylresorcinol and 4-phenylethylresorcinol.
  
  
  CONCLUSIONS
  The present in vitro and in vivo data prove the high inhibitory capacity of 4-n-butylresorcinol on human tyrosinase activity, exceeding by far the potency of hydroquinone, arbutin and kojic acid. The resulting clinical improvement of skin hyperpigmentations reveals 4-n-butylresorcinol as a very valuable active compound for the management of pigmentation disorders.
authors.affiliation: Research and Development, Beiersdorf AG, Hamburg, Germany. ludger.kolbe@beiersdorf.com
authors.forename: L
authors.initials: L
authors.lastname: Kolbe
authors.forename: T
authors.initials: T
authors.lastname: Mann
authors.forename: W
authors.initials: W
authors.lastname: Gerwat
authors.forename: J
authors.initials: J
authors.lastname: Batzer
authors.forename: S
authors.initials: S
authors.lastname: Ahlheit
authors.forename: C
authors.initials: C
authors.lastname: Scherner
authors.forename: H
authors.initials: H
authors.lastname: Wenck
authors.forename: F
authors.initials: F
authors.lastname: Stäb
mesh_terms: D000287:Administration, Topical; D000368:Aged; D001104:Arbutin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006873:Hydroquinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017495:Hyperpigmentation / Q000188:drug therapy* / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012118:Resorcinols / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D016037:Single-Blind Method; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D062327:Skin Lightening Preparations / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D046509:Tissue Culture Techniques; D016896:Treatment Outcome
chemical_list: C508220:4-n-butylresorcinol; D006873:Hydroquinones; D008543:Melanins; D011753:Pyrones; D012118:Resorcinols; D062327:Skin Lightening Preparations; C011890:kojic acid; D001104:Arbutin; D014442:Monophenol Monooxygenase; C031927:hydroquinone