Toxicological Control Mechanisms of Human CYP1A2

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DESCRIPTION: (Adapted from the Applicant's Abstract): Cytochrome P450 (CYP) enzymes play an important role in the metabolism of endogenous compounds and such exogenous substrates as drugs and various chemical carcinogens. CYP 1 A, one of the CYP subfamilies in vertebrates consisting of two members, CYP1A1 and CYP1A2, catalyzes the metabolism of such environmental chemicals as polycyclic aromatic hydrocarbons and arylamines as well as numerous drugs. Several factors appear to modulate the expression of CYP1A enzymes including chemicals (e.g. polycyclic aromatic hydrocarbons and halogenated hydrocarbons), dietary constituents (e.g. heterocyclic amines, flavones, indoles) and genetic factors. In the present research proposal, we will examine the hypothesis that the molecular mechanisms involved in the regulation of human CYP1A2 involves complex interactions of trans-acting factors at multiple and redundant regulatory elements, and that naturally-occurring dietary flavonoids alter the expression of both CYP 1 A2 and CYP IA 1. Our goals for the forthcoming grant period are to focus on the fundamental mechanistic events defining CYP1A2 basal and cell type-specific expression, and to define the role of naturally occurring dietary flavonoids in modulating CYP1A gene expression through the interactions of these agents with transcription factors (e.g. arylhydrocarbon receptor, other basic helix-loop-helix proteins) that potentially mediate human CYP1A gene expression. To this end, we will use various cell lines for in vitro studies, and we will develop models to study the molecular mechanisms involved in the in vivo regulation of human CYP1A gene expression. In vivo studies will utilize genome-integrated reporter gene constructs and a transgenic mouse line containing a bacterial artificial chromosome expressing the human CYP1A1 and CYP1A2. The long-term goals are to understand at the cellular and molecular level the mechanisms controlling the expression of CYP1A2 and the mechanisms that affect both CYP1A1 and CYP1A2 in relation to the chemoprotective properties of naturally occurring flavonoids. Additionally, understanding the molecular events associated with altered CYP1A gene expression due to interactions of such "natural" pharmaceuticals as flavonoids and other plant-derived products should lead to an awareness of possible adverse effects.