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Metabolism of xenobiotics
- 1. Xenobiotics A xenobiotic (Greek xenos ="stranger") is a chemical substance found within an organism that is not naturally produced by or expected to be present within. Xenobiotics can produce a variety of biological effects including- • Pharmacological responses • Toxicity • Immunological responses • Cancers
- 2. Xenobiotics Xenobiotics can be: a) Exogenous b) Endogenous
- 3. Xenobiotics a) Exogenous:- The foreign molecules which are not normally ingested or utilized by the organism but they gain entry through dietary food , or in the form of certain medicines/ drugs or are inhaled through environment . Examples- Drugs, food additives, pollutants, insecticides, chemical carcinogens etc.
- 4. Xenobiotics b) Endogenous:- They are not foreign substances but have effects similar to exogenous xenobiotics. These are synthesized in the body or are produced as metabolites of various processes in the body. Examples- Bilirubin, Bile acids, Steroids, Eicosanoids and certain fatty acids.
- 6. Metabolism of Xenobiotics Metabolism of xenobiotics occurs in two phases: Phase 1: The major reaction involved is hydroxylation. In addition to hydroxylation, a wide range of reactions also take place including- • Deamination • Dehalogenation • Desulfuration • Epoxidation • Reduction
- 7. Phase 2: The hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with: • Glucuronic acid • Sulfate • acetate • Glutathione • Certain amino acids • By methylation.
- 8. Detoxification / Bio-transformation Reactions: • All the biochemical reactions involved in the conversion of foreign, toxic and water insoluble molecules to non toxic, water soluble and excretable forms are called Detoxification / Biotransformation reactions. • The overall purpose of the two phases of metabolism of xenobiotics is to increase their water solubility (polarity) and thus excretion from the body.
- 9. Overview of biotransformation reactions • Phase 1 reactions can limit the toxicity of a drug. • Phase 1 reactions can also convert xenobiotics from inactive to biologically active compounds. • Phase 2/conjugation reactions can convert the active products of phase 1 reactions to less active or inactive species, which are subsequently excreted in the urine or bile. • In a very few cases , conjugation may actually increase the biologic activity of a xenobiotic (Metabolic activation).
- 11. Phase 1 Reactions Phase I reactions include: • Oxidation • Reduction • Hydrolysis reactions • They are also called Hydroxylation reactions since they introduce or expose a functional group (e.g., -OH).
- 12. A) Oxidation: A large number of foreign substances are destroyed by oxidation in the body. Examples:- • Oxidation of Aromatic Hydrocarbons: Aromatic hydrocarbons are oxidized to phenolic compounds, which can further be conjugated with Glucuronic acid or Sulfuric acid in phase 2 reactions so as to be excreted through urine.
- 13. • Oxidation of Alcohols: Primary aliphatic and aromatic alcohols are oxidized to corresponding acids, Methanol → Formaldehyde → Formic acid Ethanol → Acetaldehyde → Acetic acid Benzyl Alcohol → Benzaldehyde → Benzoic acid
- 14. B) Reduction: Reduction does not occur extensively in human beings. Examples:- • Reduction of Aldehydes: Chloral → Trichloro ethanol Trichloro ethanol is excreted after conjugation with D Glucuronic acid as corresponding glucuronide.
- 15. • Reduction of Nitro compounds: p- nitrobenzene → p- Amino benzene p- nitro phenol → p-Aminophenol
- 16. C)Hydrolysis: Certain therapeutic compounds undergo hydrolysis. Examples:- 1. Acetyl Salicylic acid → Acetic acid + Salicylic acid 2. Atropine → Tropic acid + Tropine 3. Digitalis → Sugar + Aglycone 4. Procaine → p- Amino Benzoic acid + Diethyl amino ethanol
- 17. C)Hydrolysis:
- 18. Phase 1 reactions- Enzymes Mainly Catalyzed by members of a class of enzymes referred to as Monooxygenases, Mixed Function oxidases or Cytochrome P450s. Other enzymes of significance are: • Aldehyde and alcohol dehydrogenase • Deaminases • Esterases • Amidases • Epoxide hydrolases
- 19. Cytochrome P450 Enzyme system The reaction catalyzed by a monooxygenase (cytochrome P450) is as follows: RH + O2 + NADPH + H+ → R-OH + H2O + NADP • RH above can represent a very wide variety of xenobiotics, including drugs, carcinogens, pesticides, petroleum products, and pollutants (such as a mixture of PCBs). • In addition, endogenous compounds, such as certain steroids, Eicosanoids, fatty acids, and retinoids, are also substrates. • The substrates are generally lipophilic and are rendered more hydrophilic by hydroxylation.
- 20. Phase 2 Reactions Conjugation: • Conjugation is a process by which the foreign molecules and their metabolites are coupled with a conjugating agent and are converted to soluble, non toxic derivatives which are easily excreted in urine. • Conjugation reactions can occur independently or can follow phase 1 (hydroxylation) reactions. • Conjugation takes place primarily in liver but can occur in kidney also. • After conjugation the products are generally rendered non toxic but in certain conditions they are left unchanged or become more toxic.
- 21. Types of Phase 2 Reactions 1. Glucuronidation 2. Sulfation 3. Acetylation 4. Methylation 5. Conjugation with Amino acids 6. Conjugation with G-SH • Some types are described as follows..
- 22. 1) Sulfation: The sulfate donor is adenosine 3'-phosphate-5’- phosphosulfate(PAPS) this compound is called "active sulfate” • The enzyme is sulfo transferase • Compounds which are conjugated with sulphate are as follows -Phenols -Indole -Steroids -Estrogen and Androgens -Tyrosine to form Tyrosine-O- Sulphate, which is required for the formation of Fibrinogen -Glycolipids, and glycoproteins
- 23. 2) Methylation: • Methylation is limited in the body • S- Adenosyl Methionine (Active Methionine )acts as a Methyl group donor • Reactions are called Transmethylation reactions • Enzymes catalyzing the reactions are Methyl transferases • Compounds conjugated by Methylation are:- 1- Nicotinamide: Nicotinamide + CH3 → N- Methyl Nicotinamide 2- p- Methyl Amino Azo benzene + CH3 → p- Dimethyl Amino Azo Benzene (Hepatic Carcinogen)
- 24. 3)Conjugation with Glutathione: • Glutathione (Υ-glutamyl-cysteinyl glycine) is a tripeptide consisting of glutamic acid, cysteine, and glycine • Glutathione is commonly abbreviated GSH (because of the sulfhydryl group of its cysteine). • A number of potentially toxic electrophilic xenobiotics (such as certain carcinogens) are conjugated to the nucleophilic GSH in reactions that can be represented as follows: R + GSH → R – S – G where R = an electrophilic xenobiotic.
- 25. • The enzymes catalyzing these reactions are called glutathione S- transferases • A variety of glutathione S-transferases are present in human tissue. They exhibit different substrate specificities and can be separated by electrophoretic and other techniques. • If the potentially toxic xenobiotics were not conjugated to GSH, they would be free to combine covalently with DNA, RNA, or cell protein and could thus lead to serious cell damage. • GSH is therefore an important defense mechanism against certain toxic compounds, such as some drugs and carcinogens.
- 26. Effects of Xenobiotics • Metabolism of a xenobiotic can result in cell injury, immunologic damage or cancer. • Cell injury (cytotoxicity) can be severe enough to result in cell death. • These macromolecular targets include DNA, RNA, and protein. • The reactive species of a xenobiotic may bind to a protein, altering its antigenicity • The resulting antibodies can then damage the cell by several immunologic mechanisms that alter normal cellular biochemical processes.