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

Abstract

Summary.-Six phenols [2(3)-t-butyl-4-hydroxyanisole (BHA), 2-t-butylphenol, 4-methoxyphenol, 4-methylmercaptophenol, t-butylhydroquinone and 2,6-di-tbutylphenol] 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 -2,6-di-t-butylphenol> 4-methoxyphenol > 2 -t -butylphenol -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 , BHA -2-t-butylphenol> t-butylhydroquinone> 4-methylmercaptophenol1>4-methoxyphenol. (5) Ability in vitro to discharge the activated oxygen complex of cytochrome P450 was: 2,6-di-t-butylphenol-,2-t-butylphenol > BHA > t-butlyhydroquinone > 4-methylmercaptophenol > 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.

Opinion of the Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) on a request from the Commission related to tertiary-Butylhydroquinone (TBHQ)

“…The induction of activities of Phase II enzymes in the Ah gene battery seems to be mediated by regulatory elements EpRE (Electrophilic Response Element) and ARE (Antioxidant Responsive Elements) and independent of the Ah receptor. Induction of hepatic glutathione-S-transferase activity (2-fold) was also demonstrated in vivo following short-term administration of TBHQ in female mice while UDP-glucuronyl transferase activity was reduced by one third (Rahimtula et al, 1982). In feeding studies on rats and dogs, no or only minor changes in enzyme activities of glucose-6-phosphatase (G-6-Pase), p-nitroanisole demethylase (pNaD) and aniline hydroxylase (AHase) were observed .…”