Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism.

The past 50 years have witnessed a monumental advance in our understanding of pharmacodynamics (what drugs do to the body) and pharmacokinetics (what the body does to drugs). In the realm of pharmacokinetics, dozens of enzymes responsible for drug biotransformation and transporters responsible for the absorption, distribution and excretion of drugs have been identified. Drug biotransformation (metabolism) is traditionally classified as either phase I or phase II. Phase I metabolism (functionalization) includes oxidation, reduction, hydrolysis and hydration. Enzymes catalyzing these reactions are found in virtually all tissues but especially in the hepato-intestinal axis. Quantitatively, however, the liver is generally considered to be the most important organ involved in drug metabolism. Located in the endoplasmic reticulum of hepatocytes is a family of heme proteins known as cytochrome P450 (P450 or CYP). CYP is the central constituent of the so-called microsomal mixedfunction oxidase system. The components of this system catalyze the splitting of molecular oxygen with one atom being inserted into the drug molecule and the other undergoing reduction to water. The human genome encodes 57 CYP proteins so there is a substantial genetic component to the process of drug metabolism [1]. Moreover, the activity of CYP enzymes can be induced or inhibited by a variety of environmental chemicals and drugs, adding to the variability in metabolism of different individuals. The products of phase I metabolism are generally more polar and more readily excreted than the parent compounds and are often substrates for phase II enzymes. Phase II metabolism involves conjugation with endogenous hydrophilic compounds to further increase polarity and water solubility and therefore drug excretion. Phase II metabolism is also subject to genetic and environmental variability. Although hepatic drug metabolism has been traditionally equated with ‘detoxification’, it is now known that in some cases highly reactive metabolites can be formed that react with crucial cellular macromolecules leading to various forms of toxicity. Although metabolizing enzymes are important in the process of drug disposition, equally important are a group of transporter proteins that are expressed in various tissues, such as the intestine, brain, liver and kidney, which modulate the absorption, distribution and excretion of many drugs. These transporters are classified as either primary, secondary or tertiary. Primary transporters are driven by energy from ATP hydrolysis, whereas secondary and tertiary active transporters are driven by an exchange of intracellular ions. Like the Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism Wen Xie, Hirdesh Uppal, Simrat P.S. Saini, Ying Mu, Joanna M. Little, Anna Radominska-Pandya, Michael A. Zemaitis