presentation, effect of genetic variation on CYP2D6 phase I reactions

1. Pharmacogenetics
Cytochrome P450
2D6
BY
RAGHAD A. ALWAELY
ALA’A F. ALWAZNI
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2. Objectives
To Define Cytochrome P450 2D6.
To know the family of P450 members
To clarify the function of Cytochrome P450 2D6
To know gene and genotype of Cytochrome P450 2D6
To clarify polymorphism of Cytochrome P450 2D6
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5. CYP 450 enzymes
 The super-family of cytochrome P450
enzymes has a crucial role in the metabolism
of drugs(Almost every drug is processed by
some of these enzymes).
 Cytochrome P450 enzymes show extensive
structural polymorphism (differences in the
coding region)
5
Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the
structural characteristics and functional relevance of the human cytochrome P450 2D6
enzyme". Drug Metab. Rev. 41 (4): 573–643

6. First pass effect
CH3 COOH
O N
H
COOH
phase I phase II
During first liver passage: extensive chemical transformation of
lipophilic or heavy (MW >500) compounds result in more
hydrophilic compound (increased water solubility) and easier to
excreted
Predominantly cytochrome P450 (CYP) enzymes are
responsible for the reactions belonging to phase I reaction
(monooxygenation) that evolved from the steroid and fatty acid
biosynthes
6
Wang B, Yang LP, Zhang XZ, Huang SQ, Bartlam M, Zhou SF (2009). "New insights into the
structural characteristics and functional relevance of the human cytochrome P450 2D6
enzyme". Drug Metab. Rev. 41 (4): 573–643

7. CYP 450 enzymes
7
Ostille DO., Warren AM., Kulkarni, J. The role of pharmacogenomic testing in
psychiatry. Aust New Zealand J Psychiatry 2014 Jan 10.

8. CYP450 iso-enzymes
 17 families of CYPs with about 50 isoforms
have been characterized in the human
genome
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9. CYP2D6
 Is polypeptide (497 a.a) enzyme that in humans
is encoded by the CYP2D6 gene
 primarily expressed in the liver. It is also highly
expressed in areas of the CNS(substantia nigra)
 responsible for the metabolism and elimination
of approximately 25% of clinically used drugs (O-
demethylation)
9
Lynch T, Price A (August 2007). "The effect of cytochrome P450 metabolism on drug
response, interactions, and adverse effects". Am Fam Physician 76 (3): 391–6.

10. CYP2D6 Substrates
 endogenous substances such as
hydroxytryptamines and neurosteroids.
 exogenous lipophilic bases & protonable
N atoms
 has higher affinity for alkaloids (plant
toxins)
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Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002). "Unique CYP2D6 activity
distribution and genotype-phenotype discordance in black Americans". Clin.
Pharmacol. Ther. 72 (1): 76–89.

13. CYP2D6 gene
 is located near CYP2D7/2D8 pseudogenes
on chromosome 22q13.1
 Alternatively spliced transcript variants
encoding different isoforms have been
found for this gene.
 shows the largest phenotypical variability
largely due to genetic polymorphism
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15. Genotype/phenotype
variability
 A patient's CYP2D6 phenotype is often clinically
determined via the administration of
debrisoquine (selective substrate) and
subsequent plasma concentration assay of the
debrisoquine metabolite (4-hydroxydebrisoquine)
 Pharmacogenomic tests are now available to
identify patients with variations in the CYP2D6
allele and have widespread use in clinical practice
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16. Genotype/phenotype
variability
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17. Genotype/phenotype
variability
17
Bradford LD (2002). "CYP2D6 allele frequency in European Caucasians,
Asians, Africans and their descendants". Pharmacogenomics 3 (2): 229–43

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20. CYP2D6 mutagenic site
Susceptible a.a changes
 Asp301(responsible for substrate binding)
 Ser304
 Thr309
 Val307
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21. Clinical & epidemiologic
significance
1.Ethiopian population expand/food
consumption
2.Drug loss of resp. in UM & increase ADR in PM
with antidepressant, antipsychotics, CA
chemotherapy, antiemetic & antiarrhythmic
3.Phenocopying effect with CYP2D6 inhibitors
4.PM disease predisposure
21
McLellan RA, Oscarson M, Seidegård J, Evans DA, Ingelman-Sundberg M (June
1997). "Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians".
Pharmacogenetics 7 (3): 187–91

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24. THANK YOU
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