ADVANCES IN MECHANISMS OF ACTIVATION AND DEACTIVATION OF ENVIRONMENTAL CHEMICALS

Environmental chemicals are both activated and detoxified by phase I a nd phase II enzymes. The principal enzymes involved in phase I reactio ns are the cytochrome P450s. The phase II enzymes include hydrolase an d the conjugative enzymes such as glucuronyltransferases, glutathione transferases, N-acetyltransferase, and sulfotransferase. Although othe r phase I and phase II enzymes exist, the present review is limited to these enzymes. Once thought to be a single enzyme, multiple cytochrom e P450 enzymes have been purified and characterized from many differen t species across the evolutionary tree. The application of molecular b iology techniques to this field has identified more than 150 cytochrom e P450 genes to date. At least 20-30 cytochrome P-450 enzymes appear t o exist in each mammalian species, and many polymorphisms in these enz ymes are being identified. The cytochrome P450 enzymes can now be expr essed in recombinant form using cDNA expression systems. The phase II conjugative enzymes add a hydrophilic moiety such as sulfate, glucuron ide, or acetate to compounds, which increases their water solubility a nd facilitates their excretion. However, conjugates of a number of com pounds also result in more reactive electrophilic species, which appea r to be the ultimate carcinogens. Many of these phase II enzymes also represent families of enzymes, and polymorphisms can affect the abilit y of these enzymes to metabolize chemicals. Whenever possible, we have reviewed knowledge of the human enzymes involved in particular pathwa ys.