Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxy-anisole and other phenols on hepatic enzyme activities in mice.

Six phenols [2(3)-t-butyl-4-hydroxyanisole (BHA), 2-t-butylphenol, 4-methoxyphenol, 4-methylmercaptophenol, t-butylhydroquinone and 2,6-di-t-butylphenol] previously shown to be inhibitors of benzo(a)pyrene-induced neoplasia, were examined for their ability to induce in vivo changes in hepatic mono-oxygenase and detoxication enzyme activities, and to act as mono-oxygenase inhibitors when added in vitro. (1) Generally it was found that cytochrome P450 levels were depressed, only 2,6-di-t-butylphenol caused a 2-fold induction (2) Mono-oxygenase activities were significantly altered; BHA and 2,6-di-t-butylphenol caused microsomes to show substantial increases in aniline hydroxylase and peroxidase activities. These microsomes, along with 4-methoxyphenol microsomes, also showed a substantial reduction in DNA binding of benzo(a)pyrene (BaP) metabolites relative to metabolism. (3) Detoxication enzymes glutathione S-transferases and epoxide hydratase were readily induced, the order of effectiveness being: BHA approximately 2,6-di-t-butylphenol greater than 4-methoxyphenol greater than 2-t-butylphenol approximately t-butylhydroquinone (4-methylmercaptophenol failed to induce). (4) In vitro ability to inhibit BaP metabolism and DNA-binding ability was: 2,6-di-t-butylphenol greater than or equal to BHA approximately 2-t-butylphenol greater than t-butylhydroquinone greater than 4-methylmercaptophenol greater than 4-methoxyphenol. (5) Ability in vitro to discharge the activated oxygen complex of cytochrome P450 was: 2,6-di-t-butylphenol approximately 2-t-butylphenol greater than BHA greater t-butylhydroquinone greater than 4-methylmercaptophenol greater than 4-methoxyphenol. The results are consistent with the theory that inhibition of neoplasia is related to inducibility of detoxication enzymes, though alterations in cytochrome P450 could play a significant role in some cases.