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Elevation of Extrahepatic Glutathione S-Transferase and Epoxide Hydratase Activities by 2(3)-tert-Butyl-4-hydroxyanisole¹

Department of Pharmacology and Experimental Therapeutics, The Johns Hopkins University School of Medicine [A. M. B., E. B., P. T.], and Department of Pathobiology, The Johns Hopkins University School of Hygiene and Public Health [Y-N. C., E. B., H. S. H.], Baltimore, Maryland 21205

Investigations in these and other laboratories have established that administration of 2(3)-tert-butyl-4-hydroxyanisole (BHA) to rodents: (a) protects a variety of target tissues against the production of tumors by a wide range of chemical carcinogens; (b) reduces the levels of mutagenic metabolites produced from benzo(a)pyrene and numerous therapeutic agents in vivo; (c) elevates the hepatic activities of microsomal epoxide hydratase and cytosol glutathione S-transferase; (d) alters the activities of other hepatic enzymes and affects the levels of some hepatic catalytic constituents; and (e) increases the concentrations of nonprotein thiol compounds in liver and several other tissues. Addition of BHA to the diet resulted in elevated glutathione S-transferase and epoxide hydratase activities in multiple extrahepatic tissues of female CD-1 mice and male Sprague-Dawley rats. In mice, glutathione S-transferase specific activities in cytosol doubled in lung and stomach and increased to 15 times control levels (with 1,2-dichloro-4-nitrobenzene as substrate) in small intestine. Microsomal epoxide hydratase specific activity toward styrene oxide doubled in mouse colon and stomach and increased to nearly 6 times control levels in small intestine. Enhanced activities of these enzymes were observed in several other mouse tissues and in rat small intestine, kidney, and lung. Dietary administration of BHA to mice led to elevations of the concentrations of nonprotein sulfhydryl compounds in the mucosa of several digestive tract tissues as well as in the urinary bladder. Epoxide hydratase is a detoxifying enzyme which inactivates numerous mutagenic epoxides. However, elevation of epoxide hydratase activity may not necessarily exert a protective function in the case of all arene oxides since at least some forms of this enzyme catalyze an essential step in the formation of carcinogenic diol-epoxides of benzo(a)pyrene. The enhancement by BHA of extrahepatic glutathione S-transferase activities and nonprotein sulfhydryl levels, and possibly also the enhancement of extrahepatic epoxide hydratase activity, may be important factors in the mechanisms by which this antioxidant protects against chemical carcinogenesis.

¹ Supported by NIH Grants GM 16492, AM 07422, and CA 18251. A preliminary account of this work has been published (8).

² To whom requests for reprints should be addressed, at Department of Pharmacology and Experimental Therapeutics, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Md. 21205.

Received 11/22/78. Accepted 4/24/79.

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