Abstract
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.
Highlights
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
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
In this paper we have examined the effect of feeding the 6 phenols, BHA, t-butylhydroquinone, 4-methoxyphenol, 4-methylmercaptophenol 2-t-butylphenol and 2,6-di-t-butylphenol on (a) liver cytochrome P450 levels and monooxygenase activities, and (b) liver Phase II detoxication enzyme activities which include glutathione-S-transferase(s), epoxide hydratase and UDP-glucuronyl transferase
Summary
(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, showed a substantial reduction in DNA binding of benzo(a)pyrene (BaP) metabolites relative to metabolism. In this paper we have examined the effect of feeding the 6 phenols, BHA (mixed isomers), t-butylhydroquinone, 4-methoxyphenol, 4-methylmercaptophenol 2-t-butylphenol and 2,6-di-t-butylphenol on (a) liver cytochrome P450 levels and monooxygenase activities, and (b) liver Phase II detoxication enzyme activities which include glutathione-S-transferase(s), epoxide hydratase and UDP-glucuronyl transferase. Incubations were carried out in 0IM Tris HCI (pH 7 5) at 37°C for 10 min and contained per ml: 150 ,ug microsomal protein, 20 nmol BaP in 5 ,ul DMSO and an NADPH-regenerating system. The reaction was carried out in a lml cuvette and contained 0-IM Tris HCI (pH 8.7) 20 nmol BaP-4,5-oxide and 0(5 mg microsomal protein
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