Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

• Published in: Toxicology and applied pharmacology 2013-02, Vol.266 (3), p.439-442
• Main Authors: Abel, E.L., Boulware, S., Fields, T., McIvor, E., Powell, K.L., DiGiovanni, J., Vasquez, K.M., MacLeod, M.C.
• Format: Article
• Language: English
• Subjects: 4-Hydroxy-nonenal; 60 APPLIED LIFE SCIENCES; Animals; Biological and medical sciences; BIOLOGICAL HALF-LIFE; BIOSYNTHESIS; BRASSICA; Carcinogen; Carcinogenesis, carcinogens and anticarcinogens; CARCINOGENS; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Chemical Warfare Agents - toxicity; Clinical trials; CYSTEINE; Electrophile; Enzyme Induction - drug effects; Enzymes; Female; Gas, fumes; Glutamate-cysteine ligase; Glutamate-Cysteine Ligase - biosynthesis; GLUTATHIONE; Glutathione - biosynthesis; Glutathione transferase; Glutathione Transferase - biosynthesis; Immunoblotting; IN VIVO; Isothiocyanates; LIGASES; Medical sciences; MICE; Mice, Inbred C57BL; Mustard gas; Mustard Gas - analogs & derivatives; Mustard Gas - toxicity; MUTAGENESIS; Mutation; MUTATION FREQUENCY; Natural product; natural products; Regulatory subunits; SKIN; Skin - drug effects; Skin - enzymology; Skin - metabolism; Sulfide; SULFIDES; Sulforafan; SULFUR; Sulfur mustard; Thiocyanates - pharmacology; Toxicology; Tumors; Vegetables
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.11.020

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. ► Sulforaphane induces increased levels of glutathione in mouse skin. ► Sulforaphane induces increased levels of GSTA4 in mouse skin. ► Sulforaphane, applied after CEES-treatment, completely abolishes CEES-mutagenesis. ► The therapeutic effect may suggest a long biological half-life for CEES in vivo.