Pesticides and Xenobiotic-Metabolizing Enzymes

Hodgson, Ernest

Abstract

The long term goal of this project is the elucidation of the mechanisms of interaction of individual pesticides and other xenobiotics, both pesticidal and non-pesticidal with the microsomal monooxygenase systems, and the effect of such interactions on living organisms, particularly mammals. Because xenobiotics may function as substrates inhibitors and/or inducers of the relatively non-specific microsomal monooxygenase enzymes, these enzymes are a focal point for potential interactions and are the primary subject of this project. Five areas are of particular concern. first, the role of methylenedioxyphenyl compounds as inhibitors and inducers of isozymes of cytochrome P-450, with particular emphasis on the structure-activity relationships for induction and interaction with the Ah receptor. This class of compound includes insecticide synergists (e.g. piperonyl butoxide), carcinogens (e.g. isosafrole) and natural constituents of food (e.g. myristicin). The second project involves the estimation of the relative roles of the FAD-containing monooxygenase and cytochrome P-450 in the monooxygenation of pesticides. These investigations will involve the use of inhibitory antibodies and purified enzymes and isozymes. The main focus of the third area is the role of these enzymes in the extrahepatic metabolism of pesticides. Although the liver is quantitatively the most important organ in xenobiotic metabolism, activation of toxicants in the target tissue may be of greater toxicological significance. The nervous system, the lung and the kidney are of primary interest. The forth area is that of gene expression in insects as it relates to the monooxygenases and their role in resistance to toxicants and insect-plant interactions. This is described more fully in Project 3. Finally, certain more immediately applied areas will be investigated. These include the effect of chronic alcohol consumption on the hepatic metabolism of pesticides and the effect of pesticides on the ability of the liver to metabolize clinical and other drugs. These latter studies will involve both in vivo experiments and experiments with isolated hepatocytes. Since the continued use of pesticides is necessary for production of food and fiber they will continue to be important environmental contaminants. Understanding their interactions with other xenobiotics is of critical health significance since the usual pattern of exposure involves simultaneous uptake of chemicals from diverse sources: air pollution, food additives, drugs, etc., as well as pesticides.