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XENOBIOTICS.pptx

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Prof Viyatprajna Acharya
Prof Viyatprajna Acharya

This document discusses the metabolism of xenobiotics, or foreign chemicals, in the body. It notes that xenobiotics are mostly lipophilic and cannot be easily cleared from the body. Their metabolism involves two phases - in the first phase enzymes like cytochrome P450 modify xenobiotics through reactions like hydroxylation and oxidation, while the second phase involves conjugating the substances to make them more water soluble and able to be excreted, through processes like glucuronidation and sulfation. Factors like genetic variability and drug interactions can impact an individual's ability to metabolize different xenobiotics. The document provides many examples of common xenobiotics and discusses how their metabolism can sometimes produce toxic effects.

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METABOLISM OF XENOBIOTICS Prof (Dr.) Viyatprajna Acharya, MD, PhD Dept. of Biochemistry
 XENOS = FOREIGN  XENOBIOTICS = Foreign chemicals  Metabolism of xenobiotics = handling of xenobiotics at cellular level  Earlier known as detoxification- a misnomer  Mostly lipophilic- hence can’t be cleared from body and accumulate.
XENOBIOTICS.pptx
Pollutant Substance that increases in quantity due to human activity and adversely affects the environment e.g. CO2, SO2 ,Pb etc
Contaminant A substance which is not present in nature but released during human activity e.g. DDT, Malathion, plastics
Xenobiotics that we come across in a single day  Toothpaste  Phenyl  Facewash  Soap  Deodorant/ anti-perspirant  Cosmetics  Food- pesticides, dyes, additives  Vehicle effluents  Industrial pollutants  The list is endless…..
XENOBIOTICS.pptx
Xenoestrogens  4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)  Butylated hydroxyanisole / BHA (food preservative)  Atrazine (weedkiller)  Bisphenol A (monomer for polycarbonate plastic and epoxy resin;  BPS- insecticides and pesticides  Antioxidant in plasticizers  Dieldrin (insecticide)  DDT (insecticide)  Endosulfan (insecticide)  Erythrosine / FD&C Red No. 3  Heptachlor (insecticide) • Phenosulfothiazine (a red dye) • Phthalates (plasticizers) • DEHP (plasticizer for PVC) emulsion polymerization; laboratory detergents; pesticides) • Polychlorinated biphenyls / PCBs (in electrical oils, lubricants, adhesives, paints) • Parabens (lotions) • Lindane / hexachlorocyclohexane (insecticide) • Methoxychlor (insecticide) • Nonylphenol and derivatives (industrial surfactants; emulsifiers for
XENOBIOTICS.pptx
Statistically significant against uncontaminated water  Samples of scratched pet bottles, baby feeding bottle was ~1000 times; BPA in climate exposed water was maximum  Hot water poured in polythene bag was worst- 1 crore times!!!
XENOBIOTICS.pptx
Metabolism  Aim is to make xenobiotic inactive or less harmful  Make them hydrophilic- easy excretion from body  2 phases  Site-liver
PHASE-I REACTION  Hydroxylation- MC type; catalysed by Cytochrome P450 enzymes (monooxygenases)  Other reactions- Hydrolysis, oxidation, reduction, deamination, Peroxidation, epi-oxidation
Oxidation reactions  Alcohol metabolism- ADH and ALDH  Oxidation may produce more toxic materials e.g. Methanol→ Formic acid Ethylene glycol → Oxalic acid
Reduction reactions  Nitro compounds are reduced and detoxified mostly  They are reduced to their amines  Aldehydes and ketones are reduced to alcohols Nitrobenzene → Aniline Picric acid → Picramic acid Para-nitrophenol → p-aminophenol
Hydrolysis  Esters, amines, hydrazines, amides, glycosidic bonds and carbamates  Aspirin, acetanilide, procaine, xylocaine, aliphatic esters, DFP
Phase-II reactions  Further modification and conjugation-makes the substance more water soluble and helps in excretion  Mostly contain hydroxyl group (-OH), amino (-NH2) and carboxyl groups (-COOH)  Acetylation  Methylation  Sulfation  Conjugation with Glycine  Conjugation with glucuronic acid
Glucuronidation  UDP glucuronic acid  Bilirubin- in presence of glucuronyl transferase BMG and BDG are produced  Other products undergoing glucuronidation- i. Acetylaminofluorene (carcinogen), ii. Aniline (dye) iii. Benzoic acid iv. Phenol v. Meprobamate
Sulphation  PAPS- 3-phospho-adenosine-5-phosphosulphate/ active Sulphur is the sulphate donor  Alcohols, arylamines, phenols are sulphonated
Conjugation with Glutathione  Glutathione-s-transferase enzyme catalyzes  Carcinogens are metabolised  ↓GSH- increased tissue damage
Acetylation  Acetyl CoA is the acetyl group donor  Acetyltransferase enzyme  INH is acetylated before excretion  Polymorphic forms- Slow and fast acetylators  Slow acetylators – more toxic effects of INH
Methylation  S-adenosyl-methionine (SAM)- methyl group donor  Enzyme –methyltransferase
Phase 3 reactions!!!  Phase 2 products are further metabolized  Rare  Conjugation with GSH
Cytochrome P 450/ Monooxygenases  Heme protein  In reduced state bind with CO and absorb light maximally at 450nm  Versatile enzyme- catalyze a wide range of products like drugs, carcinogens, pesticides etc. and endogenous metabolites- FA, eicosanoids, steroids etc
 Present in ER of liver  Inducible enzymes  Phenobarbiturates are the chief stimulators  Human genome codes for 14 families of Cyt P450  150 isoforms in different tissues  6 isoforms of Cyt P450- wide overlapping substrate specificity  Cyt P 450- Hydroxylation reaction and uses NADPH  Ubiquitous in all tissues  Majority- liver and intestine; 20% of total proteins in liver microsome  Adrenal gland- mitochondria also contains- involved in cholesterol biosynthesis
Mechanism of induction of Cyt-P450  mRNA transcription  mRNA stabilization  Enzyme stabilization
Nomenclature
Some isoforms show genetic polymorphism  CYP2A6- metabolises nicotine  Some allelic forms are poor metabolizers  People having this have always high nicotine content in their blood- hence saved from nicotine addiction
Factors affecting metabolism of xenobiotics  Species difference Enzyme activities may vary Age and gender Genetic make-up Inducers & inhibitors
XENOBIOTICS TOXICITY  Reactive metabolites  Mutation-carcinogenesis  Xenobiotics may themselves become carcinogens  Act as hapten-immunogenicity  Epoxide derivatives- dihydrodiols- highly reactive and mutagenic
For more PPT on Medical Biochemistry- www.drvpacharya.com
For more PPT on Medical Biochemistry www.drvpacharya.com

More Related Content

XENOBIOTICS.pptx

  • 1. METABOLISM OF XENOBIOTICS Prof (Dr.) Viyatprajna Acharya, MD, PhD Dept. of Biochemistry
  • 2.  XENOS = FOREIGN  XENOBIOTICS = Foreign chemicals  Metabolism of xenobiotics = handling of xenobiotics at cellular level  Earlier known as detoxification- a misnomer  Mostly lipophilic- hence can’t be cleared from body and accumulate.
  • 4. Pollutant Substance that increases in quantity due to human activity and adversely affects the environment e.g. CO2, SO2 ,Pb etc
  • 5. Contaminant A substance which is not present in nature but released during human activity e.g. DDT, Malathion, plastics
  • 6. Xenobiotics that we come across in a single day  Toothpaste  Phenyl  Facewash  Soap  Deodorant/ anti-perspirant  Cosmetics  Food- pesticides, dyes, additives  Vehicle effluents  Industrial pollutants  The list is endless…..
  • 8. Xenoestrogens  4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)  Butylated hydroxyanisole / BHA (food preservative)  Atrazine (weedkiller)  Bisphenol A (monomer for polycarbonate plastic and epoxy resin;  BPS- insecticides and pesticides  Antioxidant in plasticizers  Dieldrin (insecticide)  DDT (insecticide)  Endosulfan (insecticide)  Erythrosine / FD&C Red No. 3  Heptachlor (insecticide) • Phenosulfothiazine (a red dye) • Phthalates (plasticizers) • DEHP (plasticizer for PVC) emulsion polymerization; laboratory detergents; pesticides) • Polychlorinated biphenyls / PCBs (in electrical oils, lubricants, adhesives, paints) • Parabens (lotions) • Lindane / hexachlorocyclohexane (insecticide) • Methoxychlor (insecticide) • Nonylphenol and derivatives (industrial surfactants; emulsifiers for
  • 10. Statistically significant against uncontaminated water  Samples of scratched pet bottles, baby feeding bottle was ~1000 times; BPA in climate exposed water was maximum  Hot water poured in polythene bag was worst- 1 crore times!!!
  • 12. Metabolism  Aim is to make xenobiotic inactive or less harmful  Make them hydrophilic- easy excretion from body  2 phases  Site-liver
  • 13. PHASE-I REACTION  Hydroxylation- MC type; catalysed by Cytochrome P450 enzymes (monooxygenases)  Other reactions- Hydrolysis, oxidation, reduction, deamination, Peroxidation, epi-oxidation
  • 14. Oxidation reactions  Alcohol metabolism- ADH and ALDH  Oxidation may produce more toxic materials e.g. Methanol→ Formic acid Ethylene glycol → Oxalic acid
  • 15. Reduction reactions  Nitro compounds are reduced and detoxified mostly  They are reduced to their amines  Aldehydes and ketones are reduced to alcohols Nitrobenzene → Aniline Picric acid → Picramic acid Para-nitrophenol → p-aminophenol
  • 16. Hydrolysis  Esters, amines, hydrazines, amides, glycosidic bonds and carbamates  Aspirin, acetanilide, procaine, xylocaine, aliphatic esters, DFP
  • 17. Phase-II reactions  Further modification and conjugation-makes the substance more water soluble and helps in excretion  Mostly contain hydroxyl group (-OH), amino (-NH2) and carboxyl groups (-COOH)  Acetylation  Methylation  Sulfation  Conjugation with Glycine  Conjugation with glucuronic acid
  • 18. Glucuronidation  UDP glucuronic acid  Bilirubin- in presence of glucuronyl transferase BMG and BDG are produced  Other products undergoing glucuronidation- i. Acetylaminofluorene (carcinogen), ii. Aniline (dye) iii. Benzoic acid iv. Phenol v. Meprobamate
  • 19. Sulphation  PAPS- 3-phospho-adenosine-5-phosphosulphate/ active Sulphur is the sulphate donor  Alcohols, arylamines, phenols are sulphonated
  • 20. Conjugation with Glutathione  Glutathione-s-transferase enzyme catalyzes  Carcinogens are metabolised  ↓GSH- increased tissue damage
  • 21. Acetylation  Acetyl CoA is the acetyl group donor  Acetyltransferase enzyme  INH is acetylated before excretion  Polymorphic forms- Slow and fast acetylators  Slow acetylators – more toxic effects of INH
  • 22. Methylation  S-adenosyl-methionine (SAM)- methyl group donor  Enzyme –methyltransferase
  • 23. Phase 3 reactions!!!  Phase 2 products are further metabolized  Rare  Conjugation with GSH
  • 24. Cytochrome P 450/ Monooxygenases  Heme protein  In reduced state bind with CO and absorb light maximally at 450nm  Versatile enzyme- catalyze a wide range of products like drugs, carcinogens, pesticides etc. and endogenous metabolites- FA, eicosanoids, steroids etc
  • 25.  Present in ER of liver  Inducible enzymes  Phenobarbiturates are the chief stimulators  Human genome codes for 14 families of Cyt P450  150 isoforms in different tissues  6 isoforms of Cyt P450- wide overlapping substrate specificity  Cyt P 450- Hydroxylation reaction and uses NADPH  Ubiquitous in all tissues  Majority- liver and intestine; 20% of total proteins in liver microsome  Adrenal gland- mitochondria also contains- involved in cholesterol biosynthesis
  • 26. Mechanism of induction of Cyt-P450  mRNA transcription  mRNA stabilization  Enzyme stabilization
  • 28. Some isoforms show genetic polymorphism  CYP2A6- metabolises nicotine  Some allelic forms are poor metabolizers  People having this have always high nicotine content in their blood- hence saved from nicotine addiction
  • 29. Factors affecting metabolism of xenobiotics  Species difference Enzyme activities may vary Age and gender Genetic make-up Inducers & inhibitors
  • 30. XENOBIOTICS TOXICITY  Reactive metabolites  Mutation-carcinogenesis  Xenobiotics may themselves become carcinogens  Act as hapten-immunogenicity  Epoxide derivatives- dihydrodiols- highly reactive and mutagenic
  • 31. For more PPT on Medical Biochemistry- www.drvpacharya.com
  • 32. For more PPT on Medical Biochemistry www.drvpacharya.com

Editor's Notes

  1. India is at higher risk due to heavy sunlight exposure (7KWH on an avg) where plastic water and food containers are freely transported. Water poured in polythene simulated hot food being carried in polythenes. Need to give a thought regarding cold drink bottles too.
  2. The stability of a given mRNA transcript is determined by the presence of sequences within an mRNA known as cis-elements, which can be bound by trans-acting RNA-binding proteins to inhibit or enhance mRNA decay.