title: Kojic acid reduces the cytotoxic effects of sulfur mustard on cultures containing human melanoma cells in vitro.
abstract: In vivo experiments have shown that melanocytes are more sensitive than keratinocytes to the cytotoxic effects of sulfur mustard when it is applied topically to pig skin.1 It has been hypothesized that this is caused by the uncoupling of the melanogenic pathway by depletion of cellular glutathione, resulting in the uncontrolled production of cytotoxic quinone free-radical species by tyrosinase.2. In the present study, the feasibility of blocking the melanogenic pathway as a means of reducing the cytotoxicity of sulfur mustard was evaluated using kojic acid. Kojic acid is a topically applied depigmenting agent that exerts its effect by acting as a slow-binding, competitive inhibitor of tyrosinase.3 Preincubation of G361 pigmented melanoma cells and mixed cultures of G361 cells and SVK keratinocytes with 2.5 mM kojic acid resulted in significant increases in the viability of these cultures as determined by neutral red (NR) and gentian violet (GV) dye binding assays for up to 48 h following exposure to 50 microM sulfur mustard. The highest levels of protection were seen in the G361 cultures, with a 26.8% increase in culture viability (NR assay) compared with the sulfur-mustard-only controls at 24 h. Preincubation of SVK cells alone with kojic acid resulted in lower increases in viability (2.5% at 24 h by the NR assay). Inhibition of the melanogenic pathway reduces the sensitivity of cultures containing pigment cells to sulfur mustard.
authors.affiliation: DSTL Porton Down, Salisbury, Wiltshire, SP4 OJQ, UK.
authors.forename: C N
authors.initials: CN
authors.lastname: Smith
authors.forename: C D
authors.initials: CD
authors.lastname: Lindsay
mesh_terms: D016227:Benzoquinones / Q000009:adverse effects; D002470:Cell Survival; D003879:Dermatologic Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology; D008543:Melanins / Q000096:biosynthesis; D008545:Melanoma / Q000473:pathology; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009151:Mustard Gas / Q000633:toxicity*; D011753:Pyrones / Q000494:pharmacology*; D013539:Simian virus 40; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D003879:Dermatologic Agents; D005609:Free Radicals; D008543:Melanins; D011753:Pyrones; C004532:quinone; C011890:kojic acid; D014442:Monophenol Monooxygenase; D009151:Mustard Gas