Benzene and Its Principal Metabolites Modulate Proinflammatory Cytokines and Growth Factors in Human Epidermal...

Benzene is an established leukemogen and hematotoxin in humans. However, the finding that benzene is a multiple-site carcinogen in rodents raises the possibility that other tissues could be susceptible to benzene-induced carcinogenicity, especially since a significant excess of squamous cell carcinomas and papillomas arise from epidermal and oral keratinocytes in benzene-exposed rats. Since inflammation and sustained hyperplasia are two integral components in carcinogenesis, the elaboration of proinflammatory cytokines and growth factors by keratinocytes might provide a mechanistic link between tumor initiation and promotion in benzene-induced cancers. We observed that the principal benzene metabolites, represented by hydroquinone, 1,4-benzoquinone, phenol, 1,2,4-benzenetriol, and catechol, significantly alters the production of transforming growth factor of (TGF)-α and interleukin (IL)-8 in human epidermal keratinocyte cultures. These cytokines represent the primary growth promoting factor and neutrophil chemotactant in the skin, respectively. Cytokine secretion correlated with the known redox potential of individual benzene metabolites and antioxidants, including dimethyl sulfoxide, 1,1,3,3-tetramethylthiourea, and N-acetylcysteine, attenuated the response. Binary combinations of selected benzene metabolites synergized in the induction of IL-8, while benzene, by itself, induced about a three-fold increase in IL-8 production. Taken together, our studies suggest that benzene and many of its phase I metabolites induce inflammatory cytokines and growth factors and this occurs through direct covalent binding or the generation of reactive oxygen species by autooxidation and reduction. The elaboration of proinflammatory cytokines and growth factors by keratinocytes in response to benzene and its principal metabolites may participate in benzene-induced skin carcinogenesis.