Mechanisms of Pesticide Interactions - Monooxygenase Enzymes

Hodgson, Ernest

Abstract

The long-term objective of this project is to elucidate the interactions of individual pesticides and other xenobiotics with the microsomal cytochrome P450 (P450) and flavin-containing (FMO) monooxygenases, and the effects of these interactions on living organisms, particularly mammals, and ultimately humans. Because P450 and FMO catalyze the initial oxidation of many xenobiotics, including pesticides, these enzymes play a pivotal role in determining the toxicity and carcinogenicity of many foreign compounds. In addition, since P450 is involved in the intermediary metabolism of critical endogenous molecules such as steroid hormones and bile acids, alterations in the P450 system can have profound physiological consequences. Project one examines the role of FMO and P450 in extrahepatic metabolism of pesticides, primarily portals of entry and target organs. The expression of specific enzyme forms which selectively metabolize compounds to toxic products at the site of action is often a determining factor in target organ toxicities and more specifically damage to certain cell types. Subprojects include: (1) characterization of FMO forms in mouse lung, including cDNA sequences and cellular distribution; (2) distribution and localization of FMO forms (and specific P450s when appropriate) in lung, kidney, skin, olfactory tissue, and central nervous system; (3) identification of factors affecting FMO levels, e.g., hormones, genetics, and age. Project two examines the effects of specific pesticides on the P450 system, and the main subprojects are (1) determining the mechanisms of P450 induction by methylenedioxyphenyl (MDP) compounds, specifically structure-activity relationships for interactions with the Ah receptor; (2) identifying P450 isozymes induced by different pesticide groups, particularly herbicides; (3) defining the molecular mechanisms of adaptation and resistance to pesticides. Project four is an applied project using information from the above studies to develop a model, based on immunohistochemical analysis of P450 induction, which can be used to assess environmental exposure to pesticides in mammals. Since the continued use of pesticides, natural or synthetic, will be necessary for the production of food and fiber for the foreseeable future, pesticides will remain important environmental contaminants. Therefore, understanding the biochemical and molecular interactions of these chemicals with living systems is pertinent to protecting human health. Moreover, knowledge gained from this research is directly applicable to understanding mechanisms of toxicity of other environmental contaminants.