American Journal of Advanced Drug Delivery www.ajadd.co.uk Review Article Xenobiotics: An Essential Precursor for Living System Dhaval K. Patel* and Dr. Dhrubo Jyoti Sen Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India Date of Receipt- 20/07/2013 ABSTRACT Date of Revision- 22/07/2013 Date of Acceptance- 24/07/2013 A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself, nor are they part of a normal diet. Natural compounds can also become xenobiotics if they are taken up by another organism, such as the uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls, or the chemical defenses produced by some organisms as protection against predators. Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics. In general, drugs are metabolized more Address for slowly in fetal, neonatal and elderly humans and animals than in Correspondence adults. The body removes xenobiotics by xenobiotic metabolism. Department of This consists of the deactivation and the excretion of xenobiotics and Pharmaceutical happens mostly in the liver. Excretion routes are urine, feces, breath, Chemistry, Shri and sweat. Hepatic enzymes are responsible for the metabolism of Sarvajanik Pharmacy xenobiotics by first activating them (oxidation, reduction, hydrolysis College, Gujarat and/or hydration of the xenobiotic) and then conjugating the active Technological secondary metabolite with glucuronic or sulphuric acid, or University, Arvind glutathione followed by excretion in bile or urine. Environmental Baug, Mehsana- xenobiotics are xenobiotic substances with a biological activity that 384001, Gujarat, are found as pollutants in the natural environment. India E-mail: dkpatel3742 Keywords: Xenobiotic metabolism, Metabolic pathways, Oxidation, @gmail.com Reduction, Hydrolysis, Secondary metabolite, Environmental xenobiotics. INTRODUCTION However, the term xenobiotics is such as dioxins and polychlorinated very often used in the context of pollutants biphenyls and their effect on the biota, American Journal of Advanced Drug Delivery www.ajadd.co.uk Patel et al______________________________________________________ISSN 2321-547X because xenobiotics are understood as XENOBIOTIC METABOLISM/DRUG substances foreign to an entire biological METABOLISM system, i.e. artificial substances, which did not exist in nature before their synthesis by Drug metabolism also known as humans. The term xenobiotic is derived xenobiotic metabolism is the biochemical from the Greek words ξένος (xenos) = modification of pharmaceutical substances foreigner, stranger and βίος (bios, vios) = or xenobiotics respectively by living life, plus the Greek suffix for adjectives - organisms, usually through specialized τικός, -ή, -ό (tic). Xenobiotics are any enzymatic systems. Drug metabolism often chemical compounds that are found in a converts lipophilic chemical compounds into living organism, but which are foreign to more readily excreted hydrophilic products. that organism, in the sense that it does not The rate of metabolism determines the normally produce the compound or consume duration and intensity of a drug's it as part of its diet. For example, in humans, pharmacological action. most drugs are part of this category, since The body removes xenobiotics by people don't produce them naturally, or xenobiotic metabolism. This consists of the consume them under normal circumstances. deactivation and the excretion of xenobiotics Xenobiotics can also be defined as and happens mostly in the liver. Excretion substances that are present in higher-than- routes are urine, feces, breath and sweat. normal concentrations, or ones that are Hepatic enzymes are responsible for the entirely artificial and did not exist before metabolism of xenobiotics by first activating they were produced synthetically by them (oxidation, reduction, hydrolysis humans. Drug metabolism is divided into and/or hydration of the xenobiotic) and then three Phases. In Phase I, enzymes such as conjugating the active secondary metabolite cytochrome P450 oxidases introduce with glucuronic or sulphuric acid or reactive or polar groups into xenobiotics. glutathione, followed by excretion in bile or These modified compounds are then urine. An example of a group of enzymes conjugated to polar compounds in Phase II involved in xenobiotic metabolism is hepatic reactions. These reactions are catalysed by microsomal cytochrome P450. These transferase enzymes such as glutathione S- enzymes that metabolize xenobiotics are transferase. Finally, in Phase III, the very important for the pharmaceutical conjugated xenobiotics may be further industry, because they are responsible for processed, before being recognized by efflux the breakdown of medications. transporters and pumped out of cells. Organisms can also evolve to A compound that is normal to one tolerate xenobiotics. An example is the co- organism may be a xenobiotic to another. A evolution of the production of tetrodotoxin commonly used example of this is the effect in the rough-skinned newt and the evolution experienced by fish that live downstream of tetrodotoxin resistance in its predator, the from the outlet of a sewage treatment plant. common garter snake. In this predator-prey Hormones produced by humans may be pair, an evolutionary arms race has produced present, even in treated water and these high levels of toxin in the newt and compounds are foreign as far as fish are correspondingly high levels of resistance in concerned1. the snake. This evolutionary response is based on the snake evolving modified forms of the ion channels that the toxin acts upon, so becoming resistant to its effects2. AJADD[1][3][2013]262-270 Patel et al______________________________________________________ISSN 2321-547X conjugated to polar compounds in Phase II reactions. These reactions are catalyzed by transferase enzymes such as glutathione S- transferase. Finally, in Phase III, the conjugated xenobiotics may be further processed, before being recognized by efflux transporters and pumped out of cells4,5. Tetrodotoxin FACTORS AFFECTING DRUG Xenobiotic metabolism (from the METABOLISM Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic The duration and intensity of pathways that modify the chemical structure pharmacological action of most lipophilic of xenobiotics, which are compounds drugs are determined by the rate they are foreign to an organism's normal metabolized to inactive products. The biochemistry, such as drugs and poisons. Cytochrome P450 mono-oxygenase system These pathways are a form of is the most important pathway in this regard. biotransformation present in all major In general, anything that increases the rate of groups of organisms and are considered to metabolism (e.g. enzyme induction) of a be of ancient origin. These reactions often pharmacologically active metabolite will act to detoxify poisonous compounds; decrease the duration and intensity of the however, in some cases, the intermediates in drug action. The opposite is also true (e.g., xenobiotic metabolism can themselves be enzyme inhibition). However, in cases the cause of toxic effects. where an enzyme is responsible for The reactions in these pathways are metabolizing a pro-drug into a drug, enzyme of particular interest in medicine as part of induction can speed up this conversion and drug metabolism and as a factor contributing increase drug levels, potentially causing to multidrug resistance in infectious diseases toxicity. and cancer chemotherapy. The actions of Various physiological and some drugs as substrates or inhibitors of pathological factors can also affect drug enzymes involved in xenobiotic metabolism metabolism. Physiological factors that can are a common reason for hazardous drug influence drug metabolism include age, interactions. These pathways are also individual variation (e.g. pharmacogenetics), important in environmental science, with the enterohepatic circulation, nutrition, xenobiotic metabolism of microorganisms intestinal flora, or sex differences. determining whether a pollutant will be In general, drugs are metabolized broken down during bioremediation, or more slowly in fetal, neonatal and elderly persist in the environment. The enzymes of humans and animals than in adults.Genetic xenobiotic metabolism, particularly the variation (polymorphism) accounts for some glutathione S-transferase are also important of the variability in the effect of drugs. With in agriculture, since they may produce 3 N-acetyltransferases (involved in Phase II resistance to pesticides and herbicides . reactions), individual variation creates a Drug metabolism is divided into group of people who acetylate slowly (slow three Phases. In Phase I, enzymes such as acetylators) and those who acetylate quickly, cytochrome P450 oxidases introduce split roughly 50:50 in the population of reactive or polar groups into xenobiotics. Canada. This variation may have dramatic These modified compounds are then AJADD[1][3][2013]262-270 Patel et al______________________________________________________ISSN 2321-547X consequences, as the slow acetylators