This document discusses xenobiotics, or foreign chemicals, and their metabolism in the body. Xenobiotics metabolism mainly occurs in the liver and involves two phases - phase I and phase II reactions. Phase I reactions use enzymes like cytochrome P450 to increase a chemical's water solubility, while phase II reactions further process chemicals through conjugation, such as by adding glucuronic acid or glutathione. Understanding xenobiotic metabolism is important for pharmacology, toxicology, and drug interactions.

1. Xenobiotics
Dr. Atif H. Khirelsied
Faculty of Medicine
International University of Africa
Khartoum, Sudan

2. Introduction to XenobioticsIntroduction to Xenobiotics
H d i f i h i l• Humans are exposed to various foreign chemicals e.g.,
drugs, food additives, environmental pollutants
• Xenos = strange, foreign
• Knowledge of xenobiotic metabolism is essential to
d t di funderstanding of:
– Pharmacology and therapeutics
D i t ti– Drug interactions
– Toxicology

3. Xenobiotics metabolismXenobiotics metabolism
• Occurs mainly in the ER of the liver.
• Involves 30 different enzymes.Involves 30 different enzymes.
• Occurs in two phases of reactions
– Phase I reactions
– Phase II reactions
• The overall purpose of the two phases is to
increase polarity (water solubility) andincrease polarity (water solubility) and
enhance excretion.

4. Xenobiotics metabolismXenobiotics metabolism
• In some cases it may increase toxicity or
carcinogenicity.g y
D ifi i i i i l d• Detoxification is inappropriately used term

5. Examples of phase I reactionsExamples of phase I reactions
• Hydroxylation
• DeaminationDeamination
• Dehalogenation
• Desulfuration
• EpioxidationEpioxidation
• Peroxygenation
• Reduction

6. Examples of phase II reactionsExamples of phase II reactions
• Conjugation with glucuronic acid
• Conjugation with glutathioneConjugation with glutathione
• Sulfation
• Acetylation
• MethylationMethylation

7. Examples of phase I reactions
• Hydroxylation
B PhenolBenzene Catechol
Aniline
Parahydroxy aniline

8. Examples of phase I reactions
• OxidationOxidation
BenzaldehydeToluene Benzoic acidBenzaldehydeToluene Benzoic acid

9. Examples of phase I reactions
• Oxidation
i idMuconic acid
Catechol
β Ketoadipic acidβ‐Ketoadipic acid
+
Succinic acidAcetyl‐CoA

10. Examples of phase I reactions
• Oxidation
Salicylic acid Gentisic acid
Homogentisic acidPhenylacetic acid

11. Examples of phase I reactions
• Concomitant oxidation‐reduction
p‐Nitrobenzaldehyde p‐Aminobenzoic acid

12. Examples of phase I reactions
• Deamination
A i iArginine

13. Examples of phase I reactions
• Decarboxylation
Cadaverine
iLysine

14. Examples of phase I reactionsExamples of phase I reactions
• Hydroxylation
• DeaminationDeamination
• Dehalogenation
• Desulfuration
• EpioxidationEpioxidation
• Peroxygenation
• Reduction

15. Isoenzymes of cytochrome PIsoenzymes of cytochrome P450
• They are mono‐oxygenases found in the liver
ER.
• They catalyze hydroxylation of reactions.
• Comprises 11 families of enzymes.p y
• Heme containing proteins that give peak
absorbance at 450 nm.

16. The overall reaction catalyzed by
CYP450
• RH + O2 + NADPH+H → R‐OH + H2O + NADP2 2
• RH represents various substances including:• RH represents various substances including:
– Pesticides
– Petroleum products
– Pollutants, e.g., polychlorinated biphenyls (PCB).
– Endogenous substances e.g., steroid hormones,
eicosanoids, fatty acids, retinoids

17. Cytochrome P NomenclatureCytochrome P450 Nomenclature
• CYP = cytochrome P450
• Arabic number = family (40% homology)Arabic number family (40% homology)
• Letter = subfamily (55% homology)
• Arabic number = Individual enzyme
• Example, CYP1A1

18. Important features of cytochrome P450
enzymes
h h i1. They are hemoproteins
2. Highly versatile and diverse
3. Widely distributed across species, including
bbacteria.
4. Highly concentrated in the SER of liver cells.

19. Important features of cytochrome P450
enzymes
5. A large number of isoforms (about 150)
discovered.
6 C i l f ili (40% i il i )6. Constitute several families (40% similarity)
and subfamilies (55% similarity).
7 Th NADPH t d b t7. They use NADPH to reduce substances.

20. Important features of cytochrome P450
enzymes
8. Certain types of CYP450 exist in the
mitochondria and use NADP‐linked flavoprotein
called adrenodoxin reductase, and iron‐sulfur
containing protein adrenodoxin.g p
9 Th t i li id i l h h tid l h li9. They contain lipids, mainly phosphatidylcholine.
10.Most enzymes are inducible.

21. Important features of cytochrome P450
enzymes
11.Certain types of CYP450 are involved in the
metabolism of carcinogens e.g. CYP1A1.
CYP1A1 metabolize polycyclic Aromatic
Hydrocarbons (PAH)
Smokers have high levels of these enzymes
12.They are polymorphic proteins

22. Polymprohism of CYPPolymprohism of CYP450
• Polymorphic forms have different kinetic
properties e.g., CYP2D6.p p g
CYP2D6 b li d b i i• CYP2D6 metabolizes debrisoquin
(antihypertensive) and sparteine
(antiarrythemic)
– Extensive metabolizers (rapid clearance)Extensive metabolizers (rapid clearance)
– Poor metabolizers (slow clearance)

23. Phase II reactionsPhase II reactions
• Glucuronidation
• Uses UDP‐GlucuronateUses UDP Glucuronate
– Enzyme gucuronyl transferase
S b i l d b i id ili– Substrates include: benzoic acid, aniline,
meprobamate, phenol, steroids.

24. Phase II reactionsPhase II reactions
• Sulfation
– Uses adenosine‐3‐phospho‐5‐pyrophosphate
(PAPS) as sulfate donor( )
Substrates include: alcohols arylamides steroids– Substrates include: alcohols, arylamides, steroids,
phenols.

25. Phase II reactions
• Sulfation

26. Phase II reactionsPhase II reactions
j i i h l hi ( )• Conjugation with glutathione (GSH)
– Uses glutathione (γ‐glutamyl‐cysteine‐glycine).
– The reaction is catalyzed by glutathione‐S‐y y g
transferase.
– Glutathione has other important functions
• Decomposition of H2O2p
• Important intracellular reductant
• Amino acid transport in the kidney

27. Phase II reactions
• Conjugation with glutathione (GSH)• Conjugation with glutathione (GSH)

28. Phase II reactions
• Conjugation with glycine

29. Phase II reactionsPhase II reactions
• Acetylation
– Uses acetyl‐CoA as acetate donor.y
The reaction is catalyzed by acetyl transferase– The reaction is catalyzed by acetyl transferase.
– Substrates include:
• Isoniazid (anti‐tuberculosis)

30. Phase II reactionsPhase II reactions
• Acetylation
AC‐HN
Sulfonamide N‐acetyl sulfonamide

31. Phase II reactionsPhase II reactions
• Methylation
– Uses S‐adenosyl‐methionine as methyl donor.y y
The reaction is catalyzed by methyl transferase– The reaction is catalyzed by methyl transferase.
– Substrates include:
• Isoniazid (anti‐tuberculosis)