PowerPoints presentation for MBBS, BDS and MD Biochemistry students

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

27. Nomenclature

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