Xenobiotics, Biotransformations, Detoxication
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Xenobiotics, Biotransformations, Detoxication
- 3. Detoxification: Biochemical process whereby the noxious substances are rendered less harmful and more water soluble Xenobiotics: Compounds which may be accidentally ingested / taken as drugs / produced in the body by the bacterial action is rendered hydrophilic. Biotransformation: Is a process whereby a substance is changed from one chemical form to another by a chemical reaction in the body • Detoxification is the process of biotransformation of a xenobiotic
- 4. Detoxification Knowledge of how to handle toxic matter at cellular level is key to learn how to survive in this adulterated and polluted world Basic to a rational understanding of Pharmacology, Toxicology, Cancer research and DRUG ADDICTION Why?
- 5. Few terms for better understanding • Toxin: Substance with harmful effects on living systems. • Detoxification: Removal / neutralization of toxic quality of toxins. • Xenobiotic: Chemical substance present within but not made within a living body – stranger to life • Toxic load: Sum Total toxins within a given living system
- 6. Few terms for better understanding • Lipophilic Toxin: Low molecular weight, non polar, fat soluble toxins. Difficult to eliminate. • Polyvinyl chloride, Bisphenols, Benzoate • Hydrophilic toxins: Water soluble, Polar toxins. Easy to be excreted. • Urea, uric acid, creatinine, bilirubindiglucuronide
- 7. Truth: Ubiquitous, too many to count, Complex interactions • Alter brain function, • Gut disturbance, • Reproductive effects, • Hormonal imbalance Inflammation, cancer, diabetes, Autoimmune disease, CVD, Renal disease and more… Consequences R MANY
- 8. Definition • Biochemical process to convert toxic lipophilic substances to less toxic or nontoxic hydrophilic form. • Easy to excrete form
- 9. What are the Source of Toxins? • Exogenous • Diet - addative • Drug - chemical • Abuse – toxins • Microbes - • Occupation – man made • Endogenous • Metabolism • Normal – urea, UA, Bilirubin • Abnormal – Acetae, formate
- 10. Bio-transformation: Substance is changed from one substance to other by a chemical reaction within the body Bio-activtion Biotransformation leading to more toxic compound than the parent -Entoxication Bio-inactivation Noxious substances rendered less harmful and more water soluble is called Detoxication and Procarcinogen / prodrug
- 11. What all needs detoxification? Food additives Toxins / Poisons Cosmotics Drugs Metabolites Chemicals / Dyes Pesticides Insecticides Many more…..
- 12. Who looks after Bio-transformations? • The liver handles 70% of the bio-transformation reactions in body. • Other sites are • Kidneys • Lungs • Skin • Intestinal cells • Endothelial cells of BBB
- 13. Factors that affect biotransformation • Diet • Age • Developmental status • Hormonal status • Disease • Functional status of Liver and Kidney • Genetics
- 14. Biotrans formation of lipophilic Toxins • Phase 1: • Reaction that add a functional group to a fat soluble toxin so the new structure can be conjugated and made hydrophilic, excretory form. • Phase 2: • Reactions that either continue the phase 1 or independent, create a water soluble compound suitable for excretion
- 15. Phase 1 Phase 2 Fat Soluble Oxidation/ epoxidation Conjugation with Glucuronic acid Reduction Conjugation with sulfate Hydrolysis Conjugation with Glutathione Acetylation Conjugation with Amino acid How does it happen ?
- 16. Phase 1 Reactions Oxidation or Hydroxylation Large number of foreign substances are destroyed by oxidation
- 17. Phase 1 Oxidation or Hydroxylation • Large number of foreign substances are destroyed by oxidation or hydroxylation • Reaction needs • Cytochrome P450 / Mono-oxygenase • Concentrated on smooth ER of liver • Heme containing enzyme • Inducible: By Phenobarbitone, Alcohol
- 18. • P450 because absorb light at 450nm • It can detoxify exogenous drugs as well endogenous steroid and eicosanoids • It is typically mono-oxygenase as it incorporates one atom of oxygen to form hydroxy derivative, Second atom is reduced to water Cytochrome - P450 RH + O2 + NADPH ROH +H2O NADP+
- 19. Mechanism of mono-oxygenase NADPH+H NADP+ NADPH- Cyt P450 Reductase Ox NADPH- Cyt P450 Reductase Red Fe+3 Fe+2 Cyt P450 Cyt P450 R-H R-OH H2O O2 50% of the medicinal drugs are metabolised by Cyt P450 OX Red
- 20. Mechanism of Cyt P450 P450 Fe+3 R-H P450 Fe+3 R-H P450 Fe+2 R-H e O2 P450 Fe+2 R-H O2 P450 Fe+2 R-H O*2 e R-OH NADPH+H NADPH-Cyt P450 Reductase 1 2 3 4 5
- 21. • CYP3A is important cytochrome P450involved in drug metabolism, because of its abundance in liver and intestine it can fluctuate by almost 400-fold due to inhibition and induction, thus leading to problems with drug dosage Iso forms
- 22. • CYP2E1, which is induced by consumption of ethanol. This may increase the risk of carcinogenicity developing from exposure to such compounds • CYP2A6, involved in the metabolism of nicotine null alleles, who have impaired metabolism of nicotine, are apparently protected against becoming tobacco- dependent smokers Iso forms
- 23. Oxidation Ethanol Acetic acid Methanol Formic acid Benzyl alcohol Benzaldehyde Benzoic acid COOHCOHOH Catechol Muconic acid COOH COOH OH OH
- 24. Oxidation Aniline P- Amino Phenol Acetanilide P- acetyl amino phenol Ingrediant of analgesic drug which relieves pain Meprobamate Hydroxy meprobamate A Tranquilizer use for psychiatric disorder Chloral (CCl3CHO) Trichloroacetic acid Used as hypnotic, converted to TCA and excreted
- 25. Epoxide An epoxide is a cyclic ether with a three-atom ring. This ring approximates an equilateral triangle, which makes it highly strained. The strained ring makes epoxides more reactive than other ethers. Oxidation
- 26. Entoxification Vinyl chloride Vinyl chloride epoxide Potent carcinogen Benzopyrine Epoxidation Potent carcinogen Glycerol Ployethelene Potent Renal toxin Converted to oxalic acid Ethylene Glycol Hyperactive
- 27. Entoxification Poly cyclic Aromatic hydrocarbon (PAH) Epoxide Potent carcinogen •Iso form of Cyt P450 i.e. P448 found in lung of cigarette smokers •Cigatette smoke PAH are converted to Tar Which is procarcinogen
- 28. Phase 1 Reactions Reduction Nitro compounds are reduced to amines Aldehyde, Ketones are reduced to Alcohols
- 29. Reduction • Less important than oxidation Picric acid Picramic acid NO2 NO2 OH NO2 NH2 NO2 OH NO2 Chloral (CCl3CHO) Trichloro ethyl alcohol Used as sedetive, reduced before excreted
- 31. Para nitro-phenol to Para aminophenol P-Nitro phenol P-Aminophenol NO2 NH2 H2 OH OH Reduction Disulfiram Di thio carbamic acid Tx for alcohollism
- 32. Phase 1 Reactions Hydrolysis Toxic molecules are broken down to smaller ones X-Y + H2O X-OH & Y-H
- 33. Hydrolysis Aspirin popular analgesic metabolised by hydrolysis Aspirin + H2O Salicylic acid + Acetic acid Acetanilide + H2O Aneline + Acetic acid Atropine + H2O Tropic acid + Tropine Psychoactive drug Digitalis + H2O Sugar + Digoxin(Aglycon )Cardiac glycoside drug
- 34. Hydrolysis Digitalis + H2O Sugar + Digoxin(Aglycon )Cardiac glycoside drug Procaine + H2O P-Amino Benzoic acid + Diethyl amino ethanol Anesthetic drug
- 35. Hydrolysis Esters Esterase Amides Amidase Glycosides Glycosidase
- 36. Phase 2 Reactions Conjugation Number of substances undergo complex formation – conjugation after phase 1 reaction, this will make them more hydrophilic and suitable for excretion
- 37. Conjugation 1. Conjgation with glucuronic acid 2. Conjugation with glycine 3. Conjugation with Sulfate 4. Conjugation with glutamine 5. Conjugation with Cysteine / Glutathione 6. Acetylation 7. Methylation
- 38. Phenol Benzoic acid Bilirubin Steroid Amide Phenyl glucuronide Benzoyl glucuronide Bilirubin diglucuronide Steroid glucuronide N-glucuronide UDP Glucuronic acid UDP Glucuronyl transferase UDP Glucuronic acid
- 39. • Many other drugs like – Morphine – Chloramphenicol – Indomethacin – Dapsone – Sulpathiazole are conjugated with Glucuronic acid Glucuronic acid
- 40. Conjugation with Glycine Cholic acid Glycocholic acid Glycine Benzoic acid Benzoyl glycine Or Hippuric acid Glycine Salicylic acid Salicyluric acid Glycine ChenodeoxyCholic acid ChenodeoxyGlycocholic acid Glycine Nicotinic acid Nicotinuric acid Glycine
- 41. Conjugation with Sulphate Indoxyl Indoxyl sulphate PAPS Phenol Phenoxy sulphate Ethereal sulphate PAPS Sketol Sketol sulphate PAPS Cyanide Sodium thiocynate Thiosulphate PAPS = Phospho adenosyl phospho sulphate
- 42. R –X + GSH GS – R + X –H Glutathione helps in conjugation reaction Isoniazide & Sulfanamide are detoxicted by Acetylation Isoniazide Acetyl-INH Sulphaniamide Acetyl sulphanilamide Acetic acid
- 43. Conjugation with Glutamine • Phenyl acetic acid + Glutamine Phenyl acetylglutamine • α -KG + NH3 – Glutamate – Glutamine • Thus in hyper ammonemia NH3 toxicity is reduced.
- 44. Methylation • Amino, hydroxy or thiol groups are methylated • SAM act as methyl group donor • O – methyl transferases enzyme 1. Epinephrine Metanephrine 2. Nor epinephrine Nor metanephrine 3. Nicotinamide N- methyl nicotinamide 4. Histamine methyl histamine 5. Pyridine N – methyl pyridine
- 45. Purpose Chemically modified Intermediate Parent compound Toxic , Lipophililc Phase 1 Phase 2 Excreted in Urine Urine Final metabolite Non-toxic, hydrophilic
- 46. Xenobiotics for some common drugs
- 53. Thank you
Editor's Notes
- Foreign compounds like food, drugs, chemical carcinogens, food additives, food preservatives, pollutants, products of micro organism needs biotransformation or detoxication to protect health of an individual.
- Though on broad sense make same meaning but they make difference on deeper sense.
- Human encounter thousands of toxic chemicals and metabolites which need to be transformed in the water soluble and non-toxic form before they are excreted out of the body.
- It is impossible to stay away from toxic chemicals / substances. As they are ubiquitous and uncountable. If they remain it is going to affect on your body and bring toxic effect in the form of abnormal physiology or disease.
- Exogenous – Knowingly or unknowingly we are exposed or consuming from external source Endogenous – many are produced in our body as part of normal metabolic intermediates.
- Good diet – exposes less toxic matter Young age positive factor in detoxication Balanced hormonal correlation help removal of toxins Healthy liver and kidney keeps body toxin free Genetic makeup of person is sometimes responsible for toxicity Disease may produce toxic or unphysiological product which has to be eliminated
- By phase 1 reaction some substances are converted in to less toxic form which then conjugate with other substance. Thus phase 1 reaction make them ready for conjugation. Phase 2 reaction generally make them water soluble form so that they are easily excreted via urine without getting deposited in lipid fraction of body.
- Enzymes of Oxidation are present in microsome and non-microsomal fraction (cytosol, mitochondria) Microsomal oxidation – cyt P450 Non-microsomal oxidation – dehydrogenase enzymes
- Liver contains many P450 isoenzymes, as it is involved in bulk of drug metabolism.
- Main compounds required for cyt P450 is NADPH and Molecular oxygen (O2). NADPH transfers electron through FAD and FeS complex. It is also called as mixed function oxygenase as it oxidise two different substrate simultaneously.
- Epoxides are acting as free oxygen radical and have carcinogenic property.
- Oxidation reaction belongs to phase 1, instead making chemical nontoxic less effective, it increases the activity and toxicity.
- Epoxidation reaction belongs to phase 1, instead making chemical nontoxic less effective, it increases toxicity. Example : Poly Aromatic Hydrocarbon present in cigarette smoke is oxidised by Cyt P488 to black TAR which is responsible for lung cancer.