Effects of phytochemicals on human CYP1A2 activity in humans and a yeast expression system: implications for aflatoxin metabolism
Aflatoxin is believed to be a primary factor in the development of hepatocellular carcinoma, which accounts for 90% of all liver cancers. In order to elicit a carcinogenic effect in humans, aflatoxin must be converted to a reactive epoxide intermediate by the cytochrome P450 enzyme CYP1A2. Studies in animals and cells have shown that bioactive components of plant foods can enhance the detoxification of aflatoxin. One proposed mechanism by which these compounds act is through reduction of CYP1A2 activity thus slowing formation of aflatoxin-8,9-epoxide. The capacity of certain phytocehmicals to decrease CYP1A2 activity warrants further investigation; however, due to obvious limitations in studying aflatoxin metabolism and detoxification in humans, several approaches are needed.
We propose two approaches to test the hypothesis that certain constituents of apiaceous (carrot-family) vegetables reduce the mutagenicity of aflatoxin through modulation of CYP1A2. The specific aims of this project are: 1) To determine, using a human CYP1A2 yeast expression system, whether addition of specific phytochemicals reduces the effect of aflatoxin on mitotic recombination; 2) To examine, using microsomes from yeast expressing human CYP1A2, whether specific phytochemicals inhibit the CYP1A2-mediated metabolism of caffeine; and 3) To design a dietary intervention to explore the mechanism by which constituents of apiaceous vegetables inhibit CYP1A2 (using caffeine as a substrate probe) in humans and whether genetic polymorphisms in CYP1A2 alter response to diet.