Toxicological interactions through which one chemical can modify the toxicity or pharmacological action of another are of increasing concern in clinical medicine and in relation to human exposures to combinations of chemicals in the environment. Many of these result from the ability of one chemical to modify (inhbit or induce) the enzyme responsible for the biotransformation of the other. The major objective of this research is to conduct in-depth studies on the mode of action of two groups of compounds [methylenedioxyphenyl (MDP) compounds and nitrogen heterocycles (NH)] known to interact with the cytochrome P-450-mediated monooxygenation of xenobiotics. Emphasis will be placed on establishing the ability of MDP compounds and NH to form spectrally observable complexes (type I, type II and type III) with cytochrome P-450 and of relating complex formation to the inhibition of selected monooxygenase activities (aldrin epoxidase, ethoxycoumarin and ethoxyresorufin dealkylase, benzo[a]pyrene hydroxylase) both in vivo and in vitro. Inhibitor selectivity towards reactions catalyzed by different isozymes of cytochrome P-450 will be investigated in reconstituted systems incorporating purified rat hepatic cytochromes P-450b and P-450c, and comparative studies with hepatic microsomes from a variety of untreated and induced (phenobarbital and Beta- napthoflavone) mammalian (rats, mice) and nonmammalian (fish, birds) species will be made. Similar studies will be carried out with midgut microsomes from control and induced southern armyworm (Spodoptera eridania) larvae. The ability of MDP compounds and NH to complex with and inhibit pulmonary monooxygenases will be studied in vitro as well as in vivo in rats exposed to appropriate aerosols, and potential inhibitory interactions with adrenal steroid 11Beta and 21-hydroxylases will also be evaluated. Additional studies will focus on the metabolism of MDP compounds in microsomes from various species and on the stability of MDP-cytochrome P-450 complexes in the presence or absence of exogenous displacers. Several new, potentially specific cytochrome P-450c inhibitors will be synthesized based on the presumably bulky steric requirements for interaction with this isozyme. Further studies will also be conducted on the ability of MDP compounds to induce AHH activity.
