title: Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog.
abstract: Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Abel
authors.forename: S
authors.initials: S
authors.lastname: Boulware
authors.forename: T
authors.initials: T
authors.lastname: Fields
authors.forename: E
authors.initials: E
authors.lastname: McIvor
authors.forename: K L
authors.initials: KL
authors.lastname: Powell
authors.forename: J
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: K M
authors.initials: KM
authors.lastname: Vasquez
authors.forename: M C
authors.initials: MC
authors.lastname: MacLeod
mesh_terms: D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis*; D005978:Glutathione / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D015151:Immunoblotting; D017879:Isothiocyanates; D051379:Mice; D008810:Mice, Inbred C57BL; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity*; D009154:Mutation; D012867:Skin / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
chemical_list: D002619:Chemical Warfare Agents; D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; C031278:2-chloroethyl ethyl sulfide; D005982:Glutathione Transferase; D005721:Glutamate-Cysteine Ligase; C016766:sulforaphane; D005978:Glutathione; D009151:Mustard Gas