Molecular Mechanism of the Xenobiotica Metabolizing Enzyme Cytochrome P-450

Abstract

It is well known that the hemoprotein cytochrome P-450 (EC 1.14.14.1) is the key enzyme for the biotransformation of xenobiotics in the mammalian organism (Rein 1973; Schuster 1977; Ullrich 1977). Depending on the chemical nature of the xenobiotic, either a detoxification or an activation is effected by this enzyme (Coon and Vatsis 1978). The enzymatic reaction is connected with a splitting of molecular oxygen and the insertion of one atom oxygen into the substrate, thus converting a hydrophobic compound into a more polar product. On the one hand the excretion of such a tranformed foreign compound is facilitated. On the other hand, however, the insertion of a reactive group into the molecule induces the possibility of covalent binding to proteins and nucleic acids resulting in toxic substances, even in the formation of mutagens and carcinogens. This biological importance of cytochrome P-450 requires the knowledge of the molecular mechanism in order to control activation and inhibition at acute and chronic intoxications and moreover for the extracorporal use of the enzyme (Cohen et al. 1977). Cytochrome P-450 is localized in the membrane of the endoplasmatic reticulum or in the inner membrane of mitochondria. Two thirds of the total content in the organism is concentrated in the liver, but it is also present in the cells of the intestinal wall, skin, kidney and in brochiolar (Clara) cells of the lung. The activation of molecular oxygen catalyzed by the enzyme requires electrons which are transferred from NADPH via cytochrome P-450 reductase (EC 1.6.4.2) to the terminal oxidase. The interaction between both functionally linked proteins is mediated by phospholipids (Estabrook and Werringloer 1979).