Chronically administered
butylated hydroxytoluene (
BHT) can enhance the formation of
carcinogen-induced lung
tumors in mice, and biotransformation of
BHT is required for this activity. In the present study, oxidative metabolism of
BHT by liver microsomes and lung
tumor promotion by
BHT in three inbred mouse strains, NGP/N, A/J and MA/MyJ, were compared. The strain order shown is the order of increasing susceptibility of these mice to
BHT tumor promotion which correlates with their increasing ability to produce a particular metabolite,
BHT-BuOH, by hydroxylation of
BHT at one of the tert-butyl groups. Chronic
BHT administration, according to the treatment regimen for promotion, selectively induced the
BHT oxidization pathway leading to
BHT-BuOH. The results suggest that formation of
BHT-BuOH leads to the
tumor promoting effects of
BHT. This hypothesis was tested directly by chronic administration of
BHT,
BHT-BuOH, and two other metabolites, 2,6-di-tert-butyl-4-hydroxymethyl
phenol and 2,6-di-tert-butyl-1,4-benzoquinone to MA/MyJ mice following a single injection of
urethane. The only metabolite that enhanced lung
tumor formation was
BHT-BuOH, and it was effective at one-fourth the effective dose of
BHT. Thus both indirect and direct evidence implicates
BHT-BuOH formation as an important step in the chain of events leading to promotion of lung
tumors.