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1 w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No z x ½ #4 B Á½ #4 B Á #4 B Á w 1I% C Á.4 D Á ³ 1IBSN% 1I% B Á 1I% E Á 1IBSN% B B w w w C w w D E w Clinical Pharmacogenomics of Drug Metabolizing Enzymes and its Clinical Application Kyung Im Kim a, Seung Hee Kim a, Ji Eun Park a, Han Jung Chae b,g Ji Sun Choi c, Wan Gyun Shin a, In Ja Son. d, Jung Mi Oh a a College of Pharmacy, Seoul national University, Seoul, , Korea b College of Medicine, Chonbuk National University, Jun-ju, , Korea c Department of Pharmacology, Samsung Medical center, Seoul, , Korea d Department of Pharmacology, Seoul National University Hospital, Seoul, , Korea Great inter-variability in drug response and adverse drug reactions is related to inter-variability of drug bioavailability, drug interaction and patient s disease and physyological state that cause change in absorption, distribution, metabolism and excretion of drugs. However, these alone do not sufficiently predict and explain inter-variability in drug response. In recent studies, it is reported that inter-variability in drug response and adverse drug reactions may largely resulted from genetically determined differences in drug absoption, distribution, metabolism and drug target proteins. Especially, the major human drug-metabolizing enzymes such as CYP450, N-acetyl tranferase, thiopurine S-methyl transferase, glutathione S-transferase are identified as the major gene variants that cause inter-individual variability in drug s response and adverse drug reactions. These variations may have most significant implications for those drugs that have narrow therapeutic index and serious adverse drug reactions. Therefore, the genetic variation such as polymorphisms in drug metabolizing enzymes can affect the response of individuals to drugs that are used in the treatment of depression, psychosis, cancer, cardiovascular disorders, ulcer and gastrointestinal disorders, pain and epilepsy, among others. This review describes the pharmacogenomics of the drug metabolizing enzymes associated with the drug response and its clinical applications. Key words Clinical pharmacogenomics, Inter-individual variability, Drug metabolizing enzyme, CytochromeP450, Phase II enzyme * e p y z d w. w, ù,, ƒ w w e ³ ƒ z w» w. w w w e Correspondence to : w w w p 56-1, Tel: , Fax: jmoh@snu.ac.kr w ƒ,» ƒ»w. kw(pharmacokinetics) w(phamacodynamics) w. kw s w, w w w w. Á Á sá w kw w» w e e w. kw» w ƒ CYP z z P-glycoprotein. wr, z sü y w» w ƒ. w 155

2 156 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 ƒ w w z w öe. w w 1950 w promaquine w x glucose-6- phophate dehydrogenase v w ³ x z ù 30 w 1). ú w Á z t s yyw ¾ x š. p z CYP450 z x ƒ j w e mw x CYP450 ù 25 w 2-7). CYP450 z ƒ ³, w x, y,, x y, y, m, e ƒ š. w z š w w w» w w w z y w ƒ f w e z»w. w ª t ƒ v v (DNA)» w ƒ z w e mw e z yw. w ywš e y w,, e» k w. w ª DNA v v» w k s» w w» w e w» w w» z œw. ** z %SVHNFUBCPMJ[JOH FO[ZNF x z x y»w p e warfarin, phenytoin, mercaptopurine e w w e. nucleotide» z 1 (phase 1) 2 (phase2) z ƒ w (Fig. 1). 1 z CYP z superfamily N-acetyl tranferase, thiopurine S-methyl transferase, glutathione S- transferase x w 2 z. Table 1 z. " z $ZUPDISPNF1FO[ZNFT Cytochrome P450 z phase I 70~80% w 2,8) ü yw w. w CYP450 z 40% ew family, 60% ew subfamily. Fig 1. Principle enzyme exhibiting a polymorphism implicated in drug metabolism. AHD alcohol dehydrogenase; ALDH aldehyde dehydrogenase; CYP cytochrome P450; DPD dihydropyrimidine dehydrogenase; NQO1 NADPH-quinone oxidoreductase; COMT catechol-o-methyl transferase; GST glutathion S-tranferase; HMT histamine methyl-transferase; NAT N-acetyl transferase; STs sulfotransferases; TPMT thiopurine methyltransferase; UGTs uridine 5'-triphosphate glucuronosyl transferase

3 z x 157 Table 1. Examples of Drug Metabolizing Enzyme Genes Associated with Drug Response Gene Drug/Drug class Cytochrome P450 Phase I Enzymes 1A2 Clozapine Warfarin 2C9 Losartan Phenytoin 2C19 Proton-pump inhibitors Codeine Metoprolol Olanzapine 2D6 Selective serotonine reuptake inhibitors Serotonine agonists Tricyclic antidepressant Phase II enzymes Isoniazid Procainamide N-acetyltranferase Hydralazine Sulfonamide UDP-glucuronosyl transferase Irinotecan Glucose 6-phosphaste dehydrogenase Primaquine Nucleotide Base Metabolizing Enzymes Thymidilate phophorylase Fluorouracil Dihydropyrimidine dehydrogenase Fluorouracil Azathiopurine Thiopurine methyltransferase Mercaptopurine ¾ ü w 57 CYP z ƒ, 42 sww steroid prostaglandin ü w 9). w CYP450 z» x CYP2A6, CYP2C9, CYP2C19, CYP2D6 CYP3A4/5 w w x x ƒ ³ 10-12). w 56%ƒ x ƒ 1 z w, 86% CYP450 šw 3). w e, ƒ»w. CYP450 z x w e» ƒ 6,7) (Table 2). 1) Cytochrome P450 2B6 CYP z CYP2B6ƒ 0.2% w» w w š šw. ù w CYP2B6» ƒ 5~20%, CYP2B6ƒ cyclophosphamide, ifosfamide w w bupropion, nevirapine, efavirenz w e z w» w š šwš. w CYP2B6*6 x w ƒ ƒw š 13). 2) Cytochrome P450 2D6 Cytochrome P450 2D6 CYP z 5% w x 20% w. CYP2D6 x CYP ƒ ³ x CYP2D6 ³ 14). CYP2D6*1 wild type z y ùkü. CYP2D6*2 CYP2D6*1 y ƒ ù s ƒ wš CYP2D6*1 CYP2D6*2 x EM(extensive metabolizer). CYP2D6*4(detective splicing) CYP2D6*5(gene deletion) z y y»w CYP2D6*10 (Pro34Ser) CYP2D6*17 (Arg296Cys) ey z y»w PM(poor metabolizer). CYP2D6 x w w, Ultra metabolizer(um) PM e EM IM(intermediate metabolizer; w» x w y x ) e { $4000~ ). w w y e.

4 158 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 Table 2. Distribution of the principle alleles of four human cytochromes P450 Allellic Frequency (%) Enzyme CYP2A6 CYP2C9 CYP2C19 CYP2D6 ND: not detected Predominant allelic variant Mutation Consequences for enzyme function Caucasians Asians Africans Ethiopians and Saoudians CYP2A6*2 Leu160His Inactive enzyme ND ND CYP2A6del Deletion No enzyme 1 15 ND ND CYP2C9*2 CYP2C9*3 Arg144Cys Ile359Leu Reduced affinity for P450 Specificity for the substrate altered ND ND ND ND CYP2C19*2 Aberrant splicing site Inactive enzyme CYP2C19*3 Premature stop codon Inactive enzyme ND 0-2 CYP2D6*2xN Gene duplication or multiduplication Increased enzyme activity CYP2D6*4 Defective splicing Inactive enzyme CYP2D6*5 Deletion No enzyme CYP2D6*10 Pro34Ser, Ser486Thr Unstable enzyme CYP2D6*17 Thr107Ile, Arg296Cys Reduced affinity for substrates Ser486Thr ND Brockmoller CYP2D6» haloperidol ù e œ w CYP2D6 w 16). CYP2D6 z» y w,, w, x y m ƒ CYP2D6 x w Table 1. Áw CYP2D6 w w w. p y w ƒ CYP2D6 w CYP2D6 phenotype. Nortriptyline CYP2D6z w 10-hydroxynortriptyline y nortriptyline w y CYP2D6 w ƒ š 17,18). UM(ultra rapid metabolizer)» CYP2D6*2 x j, s x w CYP2D6 y ùkü» nortriptyline n e x 19). x w» w PM(poor metabolizer) 30~50mg w UM 500mg w. nortriptyline w y UM txx w ³ Huddinge University Hospital w e y e w y UM txx 10 šw 20). w UM w CYP2D6 w» paroxetine nortriptyline y w öe š 21). Áw w w CYP2D6» e y UM PM ƒw 22). PM y e» e ƒƒ. w zw EM y PM y qk (Parkinsonism-like side-effects) x PM y qk e 4 šw 23). w perphenazine, thioridazine w e z, PM y z ƒ š. ù CYP2D6 x (tardive dyskinesia), ¼ (acute dystonia), z (extrapyramidal symptoms) (akathisia) yw ³ 24). Áw m Ondansetron, tropisetron 5-HT3 ¼w w m z ƒ CYP2D6 txx w ƒ ³., CYP2D6 y x w y 5-HT3 ¼w x ƒ û w z m xw š 25). Á x y e CYP2D6 š w PM

5 z x 159 w. wx perhexiline monohydroxylation CYP2D6 w, CYP2D6 PM EM w 100 û CYP2D6 y 26). Perhexiline w EM, PM perexiline e z ƒ w 27). CYP2D6 x perexiline v x ƒ w w 28). CYP2D6 ¼w w sww y ƒ EM PM j [29.30]. Hamelin EM CYP2D6» metoprolol w x w diphenhydramine(cyp2d6 ¼w w ) n šw 31). w CYP2D6 w EM txx PM ò EM k. Á m CYP2D6 x e w (prodrug). PM e y y j w. codeine m yz» w CYP2D6 w morphine w 32), tramadol CYP2D6 w y O-desmethyltramadol w 33). CYP2D6 PM w z mz x 34.35). PM CYP2D6» z w codeine, oxycodone, hydrocodone r û d ƒ š. r û PM w w w y ƒ y j w PM w 36). CYP2D6 PM r û ƒ, r û e û EM PM y j» w CYP2D6 w fluoxetine 1 20 mg w 37). 3) Cytochrome P450 2C19 CYP2C19 x w x CYP2C19*2(aberrant splice site) CYP2C19*3(premature stop codon) CYP2C19z y y PM»w. CYP2D6 x CYP2C19» ƒ caucasian û (Asian PM 13~20% vs. Caucasian PM 2~6%) 38), CYP2C19 x w ƒ». CYP2C19 x. Á y e p x w e CYP2C19 txx w. w CYP2C19» omeprazole n, CYP2C19 PM EM w omeprazole AUCƒ 12 šw 39). w û (20mg) omeprazole n w e EM 25%, IM 50% š PM 100%, z e w x v wš 40). w 41). CYP2C19 w x helicobacter pylori e omeprazole amoxicillin sww omeprazole, amoxicillin, clarithromycin sww e z e x x EM ƒƒ 60% 29% w PM 100% 42). EM e 41%, e 74~83% H. Pylori, w 15 PM e 100% e 43,44). w CYP2C19 x 8 20 mg omeprazole n w z ü ph y w EM , IM , PM ph 6¾ ƒ ƒ. w k w CYP2C19 x y e ƒ f w» 45). Áw CYP2D6 x w, CYP2C19 x k serotonin(5-ht) (SSRIs) w öe. SSRI sertraline e CYP2C19 PM y w ƒ m x» w 46). Citalopram w CYP2C19 x w 47). 4) Cytochrome P450 2C9 Warfarin, phenytoin, tolbutamide CYP2C9 w e ƒ. Á x y e w š warfarin coumarol CYP2C9. Warfarin racemic yw S-isomerƒ CYP2C9 w. CYP2C9 x sx k warfarin w w öe ³ w 48). CYP2C9*2(Arg144Cys) CYP2C9*3(Ile359leu) ƒ CYP2C9, z y w e ey»w 49).

6 160 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 warfarin e y w CYP2C9*3 w S-warfarin wild type 90% w 50). CYP2C9*2 *3 xx w y w wild-type y w s³ ƒƒ 21% 34% warfarin ƒ v w CYP2C9*2 *3 w w y 60~75% ƒ 51). w x warfarin e w warfarin yw CYP2C9 wild-typey 95, x xw š. e» CYP2C9 x y w w y p warfarin e w ƒe 52). w CYP2C9 x šx e irbesartan e z w öe 53). Á e Phenytoin CYP2C9 w phenytoin CYP2C9 x ƒ. CYP2C9 w x w y phenytoin n z CNS w 54). e valproate CYP2C19 x w, p valproate x x w x ³ 47,55). ù w w v w. 5) Cytochrome P450 2A6 CYP2A6 x CYP2A6*1(wild type), CYP2A6*2 (single amino acid substitution), CYP2A6*3( y), CYP2A6*4A CYP2A6*4B CYP2A6*4D(3-gene deletion) w ³ 56). CYP2A6 w w, (20%) sww Caucasian(1%) j PM»w 56,57). Á Nicotine CYP2A6 w CYP2A6 x 58). CYP2A6 wx CYP2A6 wx w v ù w w 58). CYP2A6 wx w nicotine nicotine w ƒ j CYP2A6 wƒ w w w» 59). 6) Cytochrome P450 3A4/5 CYP3A z CYP3A4, CYP3A5, CYP3A7 ³. w CYP3A z w ƒ t w CYP z ü CYP 30%. w v s t w w n w öe 60). ü CYP3A y w ( 5~10 ) 61) 40~50%ƒ CYP3A z w y w, CYP3A z w y d w 62). CYP3A4 ü CYP z, 3A5 w. Exon 7 12 e ey CYP3A4» nifedipine y w ƒ ƒ š ³ y v w 11). CYP3A5 v e 60 % Caucasian 33% x. CYP3A5*1 x CYP3A5*3(aberrant splice site)» CYP3A5 z y ùkü 12). Á bioflavonoid( naringin) furacoumarin w w, w p ü CYP3A4 y w w., y w š ƒ k 63~65). Á v Rifampicin rifabutin CYP3A z g v ü estradiol norethisterone ƒ k v z k 66). (Table 3) # z 2 z,, bilirubin hormone üá 1 glucuronidation, sulfation, acetylation, methylation, glycine conjugation, glutathione conjugation mw w. 2 z y w z e w. 1) Thiopurine S-methyl transferase(tpmt), dehydropirymidine dehydronase(dpd), UDP-glucuronosyl transferase(ugt) TPMT TPMT*3A(ƒ w), TPMT*2, TPMT*3C 3ƒ x ƒ. TPMT x y mercaptopurine e ƒw x k ƒ. w DPD 5-fluorouracil

7 z x 161 Table 3. Examples of the clinical impact of CYP450 pharmacogeneticsa Disease Enzyme % of dose b Examples Depression CYP2C9 CYP2C19 CYP2D Bipolar disorder and valproate PMs and SSRIs Non-responder (UMs) and side effect of tricyclic antidepressants (PMs) Psychosis CYP2D Haloperidol and parkinsonian side effects; oversedation and perphsnazine, thoiridazine Ulcer CYP2C19-20 Dosing of PPIs; ph and gastrin changes Cancer CTP2B6 - - Cyclophosphamide metabolism CYP2D Non-response to anti-emetic drugs (UMs) Cardiovascular CYP2C9-30 Warfarin dosing; irbersatan and BP response CYP2D Perhexiline neuropathy and hepatotoxicity Pain CYP2D6 - - Codeine, no response (PMs) Epilepsy CYP2C9 - - Phenytoin, pharmacokinetics and side effects a Abbreviations: CYP, cytochrome P456; PMs, poor metabolizer; PPIs, proton pump inhibitors; SSRIs, selective serotonin reuptake inhibitors; UMs, ultrametabolizers; BP, blood pressure b The doses shown for depression and psychosis are weighted as related to the size of samples in all studies published, as reviewed by Kirchheiner et al. 46). The other doses are based on data presented in the main text. All doses are percentage of the normal dose. w DPD w x ƒ y 5- fluorouracil w w, xw 67,68). Camptothecin irinotecan (CPT- 11) carboxyl esterase w w topoisomerase I w SN-38 y. CTP-11 w SN- 38 x UDP-glucuronosyl z (UGT1A1) mw glucuronidation y y. UTG1A1 promoter x (TA)7TAA x»w wild type (TA)6TAA x û z y (TA)7TAA x x ƒ y SN-38 glucuronidation y 69). SN-38 w 70) (TA)7TAA x w y ü SN-38 ƒ ƒ CTP-11 ƒ ú. w (TA)7TAA x x x ƒw y x x w w x y 71) 2) NAT(N-acetyltransferase) NAT w acetylation arylamine 2, NAT yyw 2ƒ (NAT1* NAT2*) chromosome 8 e ƒƒ w 72). NAT1 py Ÿ ƒ s³ 66)., NAT2 coding region point mutation w x ƒ, w w slow fast txx 73). Risch 189 Ÿ y 59» y w Caucasian fast slow NAT2 acetylator x w 74). slow N-acetylatoion x ƒ Ÿ ƒ ³ w. NAT2 x hydrazine ³ 75,76) hydrazine ü»ƒ NAT2 slow x ƒ intermediate rapid x ¼ šw. NAT2 x y w w ü l w w w. *** Cytochrome P450 z, N-acetyl tranferase, thiopurine S- methyl transferase, glutathione S-transferase 1 2 z ƒ z» y w kw w w. w x, y,, x y, y, m, e w. ª w w DNA v v» w k s» w w» w e ƒ f w. e š ƒw w TDM(Therapeutic Drug Monitoring) w w z wì z dw w y ww e ƒ w w» š. ƒ x š w k e z y wì, e»»w.

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