Agaricus bisporus the mushroom of commerce, contains genotoxic arylhydrazines and arenediazonium ions. In vitro, in cellular systems, and in vivo, arylhydrazines which are metabolically converted to arenediazonium ions and aryl radicals cause DNA damage that correlates with arylhydrazine or arenediazonium ion genotoxicity. The biochemical processes which connect the arenediazonium ion and genotoxicity has not been elucidated. We show here that arenediazonium ions induce AP-I (activator protein) in a dose-dependent manner in murine epidermal JB6p* cells. Co-treatment with the antioxidant N-acetylcysteine (NAC) inhibits AP-I induction and ESR spin-trapped aryl radicals. Acetylsalicylic acid (aspirin), however, does not induce AP-I nor does it quench aryl radical formation. In transgenic mice, selective AP-I induction was observed in the lung, a target tissue. Thus, activation of AP-l, caused by DNA damage and aryl radicals, may be involved in arylhydrazine genotoxicity.