Many organic compounds, when administered to laboratory animals, induce a number of hepatic enzyme activities. Several patterns of enzyme induction, i.e. distinctive pleiotropic responses are produced by xenobiotics, and these compounds can be classified on this basis. We are interested in three classes of xenobiotics: 1) 2,3,7,8-tetrachlorodibenzo-p-dioxins (TCDD) and related halogenated aromatic hydrocarbons; 2) phenobarbital and phenobarbital-like inducers; and 3) 2(3)-tert-butyl-4-hydroxyanisole (BHA). The induction of the microsomal monooxygenase, aryl hydrocarbon hydroxylase (AHH) activity, and other coordinately expressed enzymes, and the characteristic toxic responses of TCDD, appear to be mediated through the stereospecific binding of TCDD to a cytosol receptor, the product of the Ah locus. We plan to study the properties of this receptor, the pleiotropic responses it mediates, and how this is related to the toxicity of TCDD. We plan to characterize the phenobarbital response and compare the responses produced by a potent new phenobarbital-like agonist. Using this radiolabeled phenobarbital-like agonist, we propose to search in vitro for a binding species, that has the properties expected of the putative receptor for phenobarbital. BHA induces hepatic epoxide hydratase and glutathione-S-transferase activities. We plan to examine related compounds and establish a structure-activity relationship. We propose to screen mice for genetic polymorphism in their responses to BHA or in the structural genes expressed by this compound.
Showing the most recent 10 out of 17 publications
