Xenobiotics Dr. Atif H. Khirelsied Faculty of Medicine International University of Africa Khartoum, Sudan
Jun 30, 2015
Xenobiotics
Dr. Atif H. Khirelsied
Faculty of MedicineInternational University of Africa
Khartoum, Sudan
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 therapeuticsD i t ti– Drug interactions
– Toxicology
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.
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
Examples of phase I reactionsExamples of phase I reactions
• Hydroxylation
• DeaminationDeamination
• Dehalogenation
• Desulfuration
• EpioxidationEpioxidation
• Peroxygenation
• Reduction
Examples of phase II reactionsExamples of phase II reactions
• Conjugation with glucuronic acid
• Conjugation with glutathioneConjugation with glutathione
• Sulfation
• Acetylation
• MethylationMethylation
Examples of phase I reactions
• Hydroxylation
B PhenolBenzene Catechol
Aniline Parahydroxy aniline
Examples of phase I reactions
• OxidationOxidation
BenzaldehydeToluene Benzoic acidBenzaldehydeToluene Benzoic acid
Examples of phase I reactions• Oxidation
i idMuconic acid
Catechol
β Ketoadipic acidβ‐Ketoadipic acid
+
Succinic acidAcetyl‐CoA
Examples of phase I reactions• Oxidation
Salicylic acid Gentisic acid
Homogentisic acidPhenylacetic acid
Examples of phase I reactions• Concomitant oxidation‐reduction
p‐Nitrobenzaldehyde p‐Aminobenzoic acid
Examples of phase I reactions• Deamination
A i iArginine
Examples of phase I reactions• Decarboxylation
Cadaverine
iLysine
Examples of phase I reactionsExamples of phase I reactions
• Hydroxylation
• DeaminationDeamination
• Dehalogenation
• Desulfuration
• EpioxidationEpioxidation
• Peroxygenation
• Reduction
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.
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
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
Important features of cytochrome P450enzymes
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.
Important features of cytochrome P450enzymes
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.
Important features of cytochrome P450enzymes
8. Certain types of CYP450 exist in the mitochondria and use NADP‐linked flavoproteincalled 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.
Important features of cytochrome P450enzymes
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
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)
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.
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.
Phase II reactions
• Sulfation
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 gtransferase.
– Glutathione has other important functions• Decomposition of H2O2p• Important intracellular reductant• Amino acid transport in the kidney
Phase II reactions• Conjugation with glutathione (GSH)• Conjugation with glutathione (GSH)
Phase II reactions
• Conjugation with glycine
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)
Phase II reactionsPhase II reactions
• Acetylation
AC‐HN
Sulfonamide N‐acetyl sulfonamide
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)