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Phenolic compounds cause depletion of GSH, oxidative stress and cytotoxicity in normal human dermal cells.
Kisin E; Smith C; Murray A; Kisin J; Kommineni C; Castranova V; Kagan VE; Shvedova AA
Toxicologist 2001 Mar; 60(1):169
Phenolic compounds are known to cause skin rashes, burns and ulceration, dermal inflammation and necrosis, irritant and allergic contact dermatitis, eczematous "black-spot" dermatitis, leukoderma and cancer promotion. In many cases, the mechanisms underlying these toxic effects are unknown. Enzymatic oxidation of phenols is an effective metabolic pathway leading to their bio-activation. We hypothesized that cytotoxic effects of phenolic compunds are due, at least in part, to generation of phenoxyl radicals, reactive intermediates of their one-election oxidation by different intracellular peroxidase activities (e.g., PGHS, myeloperoxidase). Phenoxyl radicals are capable of depleting the intracellular pool of GSH and oxidizing protein sulfhydryls. To experimentally test this hypothesis we measured cell viability, peroxidation, intracellular levels of GSH and protein SH-groups in six human cell lines: keratinocytes, melanocytes, fibroblasts, astrocytes, dendritic, and Jurkat cells exposed to twelve phenolic compunds. Western blot analysis of PGHS-2 in cultured keratinocytes after a single application of 2-methoxy-4-propenylphenol for 6 or 18 h showed that the protein level was elevated about 2-fold over control. We found that 18 h incubation of cultured cells in the presence of some phenolic compounds (100-500 uM) caused pronounced cytotoxicity and significant depletion of GSH. Incubation of ascorbate-preloaded keratinocytes with phenols produced an EPR-detectable signal of ascorbate radicals, indicating that redox-cycling of phenoxyl radical is likely involved in oxidative effects. In summary, while phenolics are known to act as radical scavengers, their enzymatic (PGHS-catalyzed) reactive intermediates, phenoxyl radicals, interact with vital intracellular thiol reductants and cause cytotoxic effects.
Phenolic-compounds; Stress; Cytotoxicity; Dermatitis; Cancer; Toxic-effects
Issue of Publication
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California