Relationship Between the Metabolism of Butylated Hydroxytoluene (BHT) and Lung Tumor Promotion in Mice

Abstract

The widely used antioxidant butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-4-methylphenol) produces acute pulmonary toxicity in mice, and also enhances the multiplicity of lung tumors in mice when chronically administered following a single dose of a carcinogen such as urethane. Evidence strongly indicates that the pulmonary effects of BHT are caused by one or more of its reactive metabolites, particularly the hydroperoxide or quinone methide products. The former, BHT-OOH (2,6-di-tert-butyl-4-hydroperoxy-4-methylcyclohexa-2,5-dienone+ ++), is later converted to free radicals by cytochrome P-450, and evidence implicating this pathway in BHT-OOH-induced cytotoxicity has been obtained using isolated rat hepatocytes. Pulmonary microsomes from mice effectively hydroxylate BHT to BHT-BuOH [6-tert-butyl-2-(hydroxy-tert-butyl)-4-methylphenol]; this metabolite was several-fold more effective than BHT as a lung tumor promoter, substantially more pneumotoxic than BHT in vivo, and more toxic to isolated rat hepatocytes and mouse bronchiolar Clara cells in vitro. These effects may be a result of oxidation of BHT-BuOH to the corresponding quinone methide, which is a highly electrophilic. The tumor promoting effects of BHT in mouse lung may be a result of selective cytotoxicity or altered signal transduction caused by radical-generating hydroperoxide and/or electrophilic quinone methide metabolites.