1Pharmacogenetics

Cytochrome P450 2D6

BY RAGHAD A. ALWAELY ALA’A F. ALWAZNI

2Objectives

To Define Cytochrome P450 2D6.To know the family of P450 members To clarify the function of Cytochrome P450 2D6To know gene and genotype of Cytochrome P450 2D6To clarify polymorphism of Cytochrome P450 2D6

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5CYP 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)

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

6First pass effect

CH3 COOHO 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

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

7CYP 450 enzymes

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

8CYP450 iso-enzymes

17 families of CYPs with about 50 isoforms have been characterized in the human genome

9CYP2D6

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)

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.

10CYP2D6 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.

13CYP2D6 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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15Genotype/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

16Genotype/phenotype variability

17Genotype/phenotype variability

Bradford LD (2002). "CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants". Pharmacogenomics 3 (2): 229–43

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20CYP2D6 mutagenic site

Susceptible a.a changes Asp301(responsible for substrate binding) Ser304 Thr309 Val307

21Clinical & 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 inhibitors4.PM disease predisposure

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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THANK YOU