Separation of early diffuse alveolar cell proliferation from enhanced tumor development in mouse lung

A/J mice given urethan (1000 mg/kg) followed by four injections of butylated hydroxytoluene (BHT) (400 mg/kg) developed within 4 mo approximately 40% more lung tumors than mice treated with urethan and given four injections of corn oil. Administration of the metabolic inhibitor piperonyl butoxide prior to BHT injection abolished overall alveolar cell proliferation although it did not completely suppress type II alveolar cell proliferation. Tumor multiplicity in those animals remained significantly higher (29%) than in corresponding controls. In mice treated with 3-methylcholanthrene repeated injections of BHT (300 mg/kg) increased tumor multiplicity by a much larger factor (500-800). Pretreatment of mice with BHT reduced the number of tumors produced by methylcholanthrene and at the same time blocked all cell proliferation following additional injections of BHT; nevertheless, BHT treatment given after methylcholanthrene again increased tumor multiplicity by the same factor (500-800%) seen in animals not made tolerant to BHT. It is concluded that the enhancing effect of BHT on lung tumor development is not due to the production of diffuse alveolar cell hyperplasia.