Phase II Metabolic Genes

Abstract

As stated previously, the purpose of the phase I oxidative activation reactions is to render xenobiotic compounds more soluble, more chemically reactive, and more easily excretable than the parent compound. Evolution has devised an ingenious mechanism for the removal of the metabolic products of the phase I detoxification reactions from cells. The mechanism involves two general steps. The first is a conjugation or coupling of the reactive intermediate with an endogenous carrier molecule, and the second is the elimination of the resulting conjugate out of the cell through the plasma membrane. The conjugation reactions, whereby a metabolite of a toxic agent (which may be more or less toxic than the parent compound) forms a covalent bond with the carrier molecule, are known as the phase II reactions. The resulting conjugates are almost always non-toxic, and because of certain properties of the carrier molecules, are easily eliminated from cells. There are only a few target carrier molecules in cells, the three most important being glucose, sulfate and glutathione. These compounds have the required attributes for serving the function of conjugation reactants. They are present in large concentrations in cells, which is vital, because for every molecule of toxicant eliminated, a molecule of carrier must also be lost. They are nucleophiles, which means that, like DNA and proteins, they can easily react with the electrophilic moieties generally found in toxic metabolites such as epoxides, diols, hydroxyls etc. Furthermore, they are themselves reactive molecules, and in their activated forms can pass through the plasma membrane thanks to specific transport systems. There is insufficient space here to expand further on the biochemistry of phase II conjugation reactions in general, which form an important area of biochemical toxicology. For the purpose of addressing how these reactions affect cancer susceptibility, the discussion will be restricted to glutathione, since the greater number of carcinogenic metabolites are eliminated by glutathione conjugation, and because the process has been extensively studied with respect to cancer susceptibility.