Indian Journal of Pharmacology 2001; 33: 147-169 EDUCATIONAL FORUM CYP2D6 POLYMORPHISM GENETIC POLYMORPHISM OF CYP2D6 *BENNY K. ABRAHAM, C. ADITHAN Clinical Pharmacology Unit, Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry-605 006. *Present address: Department of Pharmaceutical Sciences, M.G. University, Cheruvandoor campus, Ettumanoor (P.O.)-686 631. Kerala Manuscript Received: 19.9.2000 Accepted: 19.2.2001 SUMMARY CYP2D6 is polymorphically distributed and is responsible for the metabolism of several clinically important drugs. It is also related to several pathophysiological conditions. Defect alleles, causing poor metaboliser (PM) phenotype and alleles with duplicated or multiduplicated active genes, causing ultra extensive metabolism (UEM) have been described. CYP2D6 polymorphism exhibits pronounced interethnic variation. While initial observation and studies focused on population of Caucasian origin, later other populations also studied extensively. Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of pharmacologically active drug or metabolite. Knowledge of individual’s CYP2D6 status may be clinically and economically important and could provide the basis for a rational approach to drug prescription. KEY WORDS Genetic polymorphism CYP2D6 pharmacogenetics INTRODUCTION CYP Genetic polymorphism is defined as the inheritance of ‘CYP’ is the abbreviation for cytochrome P-450, a a trait controlled by a single genetic locus with two alle- subgroup of related enzymes or isoenzymes located les, in which the least common allele has a frequency in the endoplasmic reticulum and expressed mainly of about 1% or greater1. One of the most extensively in the liver. It is also present in other organs, such as studied genetic polymorphisms known to influence drug the intestine and the brain4. In mammals, most metabolism and response is the debrisoquine type xenobiotics are metabolised via hepatic phase 1 (CYP2D6) oxidation polymorphism. The discovery of metabolism by means of CYP monooxygenases5. CYP2D6 polymorphism created new interest in the role Thirty or more different forms of these haem thiolate of pharmacogenetics in clinical pharmacology2. proteins have been characterized in humans3. The Genetic polymorphism has been linked to three P450 superfamily is composed of families and sub- classes of phenotypes based on the extent of drug families of enzyme that are defined solely on the basis metabolism. Extensive metabolism (EM) of a drug is of their amino acid sequence similarities. With few characteristic of the normal population; poor metabo- exceptions, a P450 protein sequence from one fam- lism (PM) is associated with accumulation of spe- ily exhibits upto 40% resemblance to a P450 from cific drug substrates and is typically an autosomal other family. P450s with in a single subfamily always 6,7 recessive trait requiring mutation and/or deletion of share greater than 55% sequence similarity . both alleles for phenotypic expression; and ultra ex- Evolution of CYP2D6 polymorphism tensive metabolism (UEM) results in increased drug metabolism and is an autosomal dominant trait aris- Between 1975 and 1977 two groups independently ing from gene amplification3. discovered the genetic deficiency of debrisoqine8 and Correspondence: C. Adithan e-mail: [email protected] 148 BENNY K. ABRAHAM AND C. ADITHAN sparteine9 metabolism. The discovery of genetic poly- with increasing numbers of alleles being detected, morphism in the metabolism of the two prototype this system is now inadequate. The general recom- drugs was not the result of a planned strategy but mendation is that the gene and allele are separated rather an incidental observation. A dramatic event in by an asterisk. Specific alleles are named by Arabic a pharmacokinetic study prompted the initial search numerals or a combination of Arabic numerals followed for a specific metabolic defect: the investigator, Dr. by a capitalized Latin letter. There are no spaces be- Smith, who was participating in a study on debriso- tween gene, asterisk and allele and the entire gene- quine, a sympatholytic antihypertensive drug, had a allele symbol is italicized (e.g. CYP2D6*1A) 13,14. much more pronounced hypotensive response than his colleagues, collapsing from a sub therapeutic Since a number of CYP2D6 alleles share common dose. This was found to be due to impaired 4- key mutations but differ with respect to other base hydroxylation of debrisoquine8. changes, these should be given the same Arabic number (denoting their allele group) and distinguished Similarly in 1975, during the course of kinetic stud- by capitalized Latin letters (denoting the allele sub ies by Eichelbaun et al with a slow release prepara- groups). For example, both CYP2D6*4A and tion of sparteine, two subjects developed side effects CYP2D6*4B have the same mutation but differ by a such as diplopia, blurred vision, dizziness and head- single silent base substitution13. ache. When analysing the plasma levels of sparteine Extra copies of an allele (duplicated or amplified) may in those subjects the reason for the development of exist in tandem; for example, the CYP2D6L2 allele side effects become evident. Compared to all the contains two copies of CYP2D6L. Here the entire other subjects studied, their plasma levels were 3 to arrangement of alleles should be referred to as 4 times higher, although the same dose had been CYP2D6*2X2. When duplication is not with the same given to every subject9. subgroup, they are separated with a coma (e.g. Family and population studies10 uncovered a genetic CYP2D6*10B,10C)13. polymorphism and later work established that the two independently discovered defects in drug oxidation A non-italicized form of the allele is used to name co-segregated in Caucasians (PM for sparteine ex- the protein with asterisk omitted and replaced by a hibit impaired debrisoquine metabolism and vice single spacing e.g.: CYP2D6 1. Both alleles italicized versa) and the term sparteine/debrisoquine and separated by slash to name the genotype des- 13,14 polymorphism was coined11. However there are ap- ignation (CYP2D6*1/CYP2D6*4A) . parent exemptions to this rule. For instance, in a study For a review of the most recent nomenclature of in Ghana, the ability of Ghanaians to oxidise sparteine CYP2D6, refer to Daly et al 13 and Garte and Crosti14. was independent of their capacity for debrisoquine This nomenclature system is also used for other P450 oxidation12. alleles like CYP2A6*1, CYP2C9*2, CYP2C19*2 etc. Descriptions of the alleles as well as the nomencla- Nomenclature ture and relevant references are continuously up- Guidelines on nomenclature for individual cytochrome dated at the new web page (http://www.imm.ki.se/ P450 isoform have been internationally agreed upon CYPalleles/). and are regularly updated. Genes encoding the P450 enzyme are designated as CYP. Because of the di- MOLECULAR GENETICS versity of the cytochrome family, a nomenclature sys- The CYP2D6 gene resides in the CYP2D6-8 clus- tem based on sequence identity has been developed ters on chromosome 22 in association with the to assist in unifying scientific efforts in this area and CYP2D7P and CYP2D8P pseudogenes15. Defective to provide a basis for nomenclature of newly recog- alleles can be the result of gene deletion16, gene con- nized members of this gene superfamily. For exam- versions with related pseudogenes and single base ple, CYP2D6 is isoform 6 of subfamily D included in mutations17 causing frameshift, missense, nonsense the 2 CYP family3. or splice-site mutations18,19. The homozygous pres- In the past, CYP2D6 alleles have been named arbi- ence of such alleles leads to a total absence of ac- trarily using a single letter after the gene name,7 but tive enzyme and an impaired ability to metabolise CYP2D6 POLYMORPHISM 149 Table 1. Inhibitors of CYP2D6. Ajmalicine Ajmaline Amitriptyline Amesergide Aprindine Budipine Bufuralol Chloroquine Chlorpromazine Cimetidine Cisthiothixene Citalopram Clomipramine Clozepine Desmethylimipramine Diphenhydramine Flecainide Fluoxamine Fluoxetine Fluphenazine Halofantrine Haloperidol Levomepromazine Methadone Meclobemide Olanzapine Oxprenolol Paroxetine Perazine Perphenazine Propofenone Propranolol Quinidine Quinine Ranitidine Reboxetine Resperidone Sertraline Terbinafine Terfenadine Thioridazine Ticlopidine Venlafaxine Yohimbine probe drugs specific for the drug-metabolizing en- of this basic nitrogen. It may also have a flat lipophilic zyme. These subjects are classified as PM16-20. region and functional groups which have capacity for electrostatic interactions or the ability to form hydro- In addition to defective CYP genes, there are also gen bonds25,26. The enzyme even shows stereose- alleles that cause diminished or altered drug metabo- lectivity also. In extensive metabolizers, inactive lism. This results in enzyme products that exhibit R-metoprolol is metabolized faster than the active impaired folding capacity and therefore the expres- S-enantiomer whereas this metabolism is not sion of the functional enzyme is severely dimin- sterioselective in poor metabolisers27. Isoform selec- ished17,18. Among extensive metabolisers, heterozy- tivity of CYP2D6 is observed in mianserin metabo- gotes (one functional gene) have higher medium lism also28. metabolic efficacy than those who are homozygous for the wild-type allele (two functional genes), but with INHIBITION