Xenobiotics Introduction Xenobiotics are organic chemical compounds which

Xenobiotics

Introduction • Xenobiotics are organic chemical compounds which are foreign substance to animal body. • These are the substances found in the organism but not producing by it. • Recent surveys reveals that 1 -3 millions of xenobiotics are exposed to humans in their lifetimes. Patterson AD, Gonzalez FZ, Idle JR. Xenobiotic metabolism-A view through the Metabolometer. Chem Res Toxicol. 2010 May, 17. 23(5): 851 -860. 2

Types of Xenobiotics • • Plant constituents Drugs Pesticides Cosmetics Flavorings Food additives Industrial chemicals Environmental pollutants Rodwell VW, Bender DA, Botham KM, kennelly PJ, Weil PA. Chapter 47: Metabolism of Xenobiotics. 30 th Edn. Harpers Illustrated Biochemistry. The Mc. Graw Hill. 3

Transport of Xenobiotics • Transport to the body through various routes – Air – Diet – Drinking water – Drug administration – Lifestyle • These are less toxic, more polar, easily execretable. Rodwell VW, Bender DA, Botham KM, kennelly PJ, Weil PA. Chapter 47: Metabolism of Xenobiotics. 30 th Edn. Harpers Illustrated Biochemistry. The Mc. Graw Hill. 4

Biomedical Importance of Xenobiotics • Help to explain modulation of homeostasis and toxicity in body. • Emergence of molecular biological tools, together with genetic engineering, genomics, transgenic models have evaluated the functional role of xenobiotics. • These are as mediators of gene and environmental interactions. Patterson AD, Gonzalez FZ, Idle JR. Xenobiotic metabolism-A view through the Metabolometer. Chem Res Toxicol. 2010 May, 17. 23(5): 851 -860. 5

Overview of Xenobiotics Metabolism Patterson AD, Gonzalez FZ, Idle JR. Xenobiotic metabolism-A view through the Metabolometer. Chem Res Toxicol. 2010 May, 17. 23(5): 851 -860. 6

Metabolism of Xenobiotics • It includes absorption, distribution, biotransformation and excretion. • Inside of the cell metabolism requires energy, cofactors, and enzymes. • Generates – Toxic species – Activates the drug – Loss of pharmacologic activity sometimes Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 7

Two Phases Phase I – Pharmacokinetic • ‘What the body does to the drug’ Phase II – Pharmacodynamic • ‘What the drug does to the body’ Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 8

Phase I 9

Absorption • Orally given drugs are absorbed from the GI tract. • Absorption mostly takes place in the small intestine. • From intestinal wall to reach blood circulation, drugs must pass liver through the portal vein. • Drugs are partially metabolized in intestinal wall and liver. Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 10

Distribution • Once the drugs absorbed into blood stream, circulates through the body. • Some drugs remain within watery tissues of blood and rest in tissues of liver and kidneys. • Rate of distribution of a drug vary person to person. Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 11

Biotransformation • Final products of metabolism are metabolites, – Similar or different – Differs in therapeutic activity – More toxic than parent drug • Enzymes in liver stimulates oxidation, reduction, and hydrolysis of drugs. • While other enzymes attach substances to drugs, results into conjugates. Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 12

Drug Metabolism via Hepatic Enzymes Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 13

Excretion • Elimination of drug from body. • Conjugated drugs are through bile entered into the GI tract and excreted through feces. • Water soluble metabolites filtered by kidney and excreted through urine. • Minute amounts of drugs are excreted in saliva, sweat, and even exhaled air. Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 14

Phase I Biotransformation Reactions Type of Reaction Mechanism Enzymes Oxidative Reactions Electron abstraction by incorporating O 2 molecule from oxygen or water Aldehyde Oxidase (AO) Xanthine Oxidase (XO) Cytochrome P 450 s Hydrolytic Reactions Water molecule breaks esters or amide bonds results carboxylic acid Carboxylicesterase Peptidase Epoxide hydrolase Cholinesterase Paraoxonase Reductive Reactions Reduction of azo, nitro, and carbonyl groups, sulfoxides, Noxides and quinones Carbonyl reductases Alcohol dehydrogenases Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 15

Phase II 16

Biotransformation • This phase concerned with result of the interaction of drug and body at its site of action, that is what the drug does to body. • Drug interaction is the process in which a substance or an external circumstance affects the action of drug. Drug + Receptor Drug-Receptor Complex Pharmacologic Response Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 17

Phase II Biotransformation Reactions Type of Reaction Mechanism Enzymes Glucoronidation Gives O-, N- and S-glucosides, xyloside, riboside UDPglucoronyltransferase (UGT) Sulfation Sulfonated functional groups are phenols, acohols, arylamines, and Nhydroxy compounds Sulfotransferase Methylation Deactivates the bilogical activity These reactions are involved with melatonin, histamine, seratonin, dopamine…etc Methyltransferase Acetylation Aromatic amines and hydrazine groups are converted to aromatic amides and hydrazides N-acetyltransferase Kamel AM. Metabolic Transformations of Xenobiotics. http: //web 2. uconn. edu/rusling/Amin. pdf. Accessed April 4, 2018. 18

Thank You 19