A number of phenolic compounds that are utilized in industry (e.g., for production of resins, paints, lacquers, cosmetics and pharmaceuticals) are toxic to skin (i.e., can cause rash, dermal inflammation, contact dermatitis, leucoderma, and/or cancer promotion). The biochemical mechanisms of dermal toxicity of phenolic compounds are not well understood. We observed alpha-phenyl-N-tert-butylnitrone (PBN) spin-trapped free radicals generated in the skin of female B6C3F1 mice after topical exposure to phenol (3.5 mmol/kg, 100 microL, 1 h). The exposure also resulted in oxidation of GSH and protein thiols, and decreased levels of total antioxidant reserves and vitamin E in the skin. We also compared the effects of phenol in mice with normal or diminished levels of GSH. The magnitude of phenol-induced PBN-spin-trapped radical adducts in skin of mice with diminished levels of GSH (either pre-treated with DL-buthionine sulfoximine, BSO, or 1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) was remarkably higher as compared to those in mice treated with phenol alone. Topical exposure to phenol also resulted in increased inflammatory cell infiltration in the skin of mice pre-treated with BSO or BCNU. To identify mediators involved in skin inflammation after phenol and phenol plus BSO exposure, we used JB-6 mouse epidermal cells. Using ELISA, we found that phenol and BSO plus phenol induced increases in IL-1Beta and prostaglandin E2> production in the cells as early as 1 h post-treatment. Real time PCR of ICAM-1 revealed mRNA expression starting at 3 h after exposure of the cells to phenol and BSO plus phenol. Additionally, western blot analysis showed higher expression of COX-2 in cells exposed to BSO plus phenol. In the skin, we also observed mRNA expression of COX-2 and IL-1Beta in mice treated for 2 h with phenol or BSO plus phenol. These data indicate that mediators, such as IL-1Beta, ICAM-1 and prostaglandin E2, are involved in early stages of skin inflammation in response to phenol and phenol plus BSO.
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah