Tissue-specific Induction Patterns of Cancer-protective Enzymes in Mice by tert-Butyl-4-hydroxyanisole and Related Substituted Phenols

Some of the anticarcinogenic effects of 2(3)-tert-butyl-4-hy-droxyanisole (BHA) are attributable to the induction of detoxifying enzymes in the liver and peripheral tissues. This study was designed to determine if the tissue specificity of enzyme induction could be manipulated by structural modification of BHA. The induction of glutathione S-transferases and quinone reductase (EC 1.6.99.2) by the component isomers of commercial BHA (major isomer, 3-BHA and minor isomer, 2-BHA), the methyl ether of BHA, tert-butylhydroquinone, and 4-hydroxyanisole was examined in the cytosols of liver, four regions of the gastrointestinal tract, lung, and kidney of female CD-1 mice. Induction patterns showed specificity with respect to chemical nature of inducer, target tissue, and enzymes elevated. Thus, 3-BHA and methyl-BHA induced both enzymes primarily in liver and upper small intestine but were inactive in forestomach; 2-BHA was a much less potent inducer than were 3-BHA and methyl-BHA in the liver and inactive in upper small intestine, but it produced a 2-fold elevation of enzymes in the forestomach, as did tert-butylhydroquinone and 4-hydroxyanisole. Only tert-butylhydroquinone raised transferases in the glandular stomach where all other compounds were ineffective. No compound examined raised enzymes significantly in the colon. 3-BHA and methyl-BHA induced quinone reductase of lung and kidney, where the other compounds were relatively less effective. The marked hepatomegaly associated with administration of 3-BHA and methyl-BHA was characterized by elevations of total DNA, RNA, and protein content suggesting a combination of hypertrophy and hyperplasia.