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.
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
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.
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.
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.
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
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)
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)