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1 Pharmacogenomics of Tamoxifen Therapy Hiltrud Brauch 1,2,a, Thomas E. Mürdter 1,2, Michel Eichelbaum 1,2 and Matthias Schwab 1,2,3 1 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany 2 University Tübingen, Tübingen, Germany 3 Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany. a Address correspondence to this author at Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany. Fax +49-(0) hiltrud.brauch@ikpstuttgart.de. Clin Chem P450 (CYP) CYP2D6 CYP2D6 CYP2D6 Poor Metabolizer Intermediated Metabolizer CYP2D6 CYP2D6 ( P450 family 2 subfamily D polypeptide 6) 1

2 CYP2D6 Early Breast Cancer Trialist Collaborative Group EBCTCG Estrogen Receptor: ER 5 (1) (1) Aromatase Inhibitors AIs (2) (3) (4) (1) 30 50% P450 Cytochrome P450 CYP CYP2D6 2

3 4-4- -N- CYP2D6 CYP2D6 CYP2D6 tans- {(Z)-2-[4-(1,2-diphenylbut-1-enyl)-phenoxy]-N,N-dimethyl-ethanamine} 1 2 N- N- N- CYP3A4 CYP3A5 CYP2D6 CYP1A1 CYP1A2 CYP2C19 CYP2B6 (5) (6) (7) 20mg 3 N g/l g/l (8) (9) (10) (11) (12) (13) (14) N- para N- CYP2D6 (15) (16) CYP2D6 8.1 g/l n g/l n 55 (17) 4-4 CYP2D6 CYP3A4 CYP2C9 CYP2B6 CYP2C19 CYP (7) (18) (19) (20) (21) endoxifen g/l 6.4 g/l (11) (14) (22) endoxifen 4-3

4 1. Hb, hemoglobin; FMO1, flavin-containing 4 monooxigenase 1

5 4' 4'- CYP2B6 CYP2D6 (7) 4'- -N- - CYP3A4 (5) (6) (23) (24) 4 in vitro E cis (25) ER 4- CYP1B1 CYP2B6 CYP2C19 7 cis- 4- (26) cis 4- CYP3A4 CYP2D6 3,4- (27) DNA (28) (29) flavin-containing monooxigenase 1 3 N- CYP2A6 CYP1A1 CYP3A4 CYP N- (30) (31) N- N- N- 15% (32) II 4- O- UDP- (UGTs) UGT1A4 UGT2B15 UGT2B7 UGT1A8 4- -O- (33) (34) (35) O UGT1A10 UGT1A8 II N + UGT1A4 (36)(37) N+ 4 UGT1A4 4 5

6 N + 4 Sulfotransferase; SULTs SULT1E1 SULT1A1 SULT2A1 (32) (38) 4- E (33) - SULT2A1 (39) - DNA (40) (41) in vitro 1 in vivo N- 4 N,N- - N- 1 CYP2D6 CYP2D6 - Top 200 Drug http // 200 April 2008 CYP3A(37%) CYP2C(33%) 15% CYP2D6 (42) CYP2D6 22 CYP2D6 CYP2D7P1 P450 2 D 7 1 CYP2D7P2 P450 2 D 7 2 CYP2D8P1 P450 2 D 8 1 CYP2D8P2 6

7 1 P450 2 D 8 2 CYP2D7 CYP2D8 (43) CYP2D

8 (44) (45) CYP2D6 / Extensive Metabolizer (EM) 30 Poor Metabolizer (PM) CYP2D6 EM Intermediated Metabolizer (IM) PM Ultrarapid Metabolizer (UM) 4 (46) (47) (48) 7 10% PM 10 15% IM UM 10% 15% PM 99% 2 20 null CYP2D6 PM DNA (42) (46) (48) (49) EM *1 *2 1 2 EM 1 2 IM PM 1 *1 *2 EM IM EM EM 50% EM IM ( *9 *10 *41 ) ( ) (47) (52) EM (47) (50) (51) (52) 2% 3% CYP2D6 (UM) mg PM UM 30 (53) (54) UM UM 20% 30% (46) (48) (55) 100 [ (56)] 15 CYP2D6 CYP2D6/CYP2D7 8

9 PM IM UM CYP2D6 [ 29% (57)] [21% (58)] (59) (60) CYP2D6*10 IM (61) 57% PM (59) CYP2D6 10% PM CYP2D6 PM IM / UM (62) (63) UM CYP2C9 2C19 2B6 3A4 3A5 2 CYP CYP2C9 CYP2C19 CYP2B6 (15) (18) CYP2C9( P450 2 C 9) 30 *2 *3 (64) *3 *2 90% (65) 35% (42) (66) 2% 24% (67) CYP2C9 CYP2C9 (68) (69) K (68) (70) (71) CYP2C9 CYP2C19 ( P450 2 C 19 ) null (CYP2C19*2 *3 *4 *5 *6 *7 *8) CYP2C19 (PM) *2 null (*2) (*3) CYP2C19 ( 9

10 ) (72)( CYP2C19 (*9 *25) CYP2C19*2 * 3 CYP2D6 PM PM 3% 23% PM / (72) (73) 32% (74) CYP2C19*17 CYP2C19 [ (75)] (76) UM in vivo CYP2C19 CYP2C19*17 18% (75) 25% (77) 27% (78) (4%) (75) / (79) CYP2C19 UM CYP2B6( P450 2 B 6) *6 15%-60% (80) CYP2B6*6 HIV (81) (82) CYP2B6*6 35% (83) CYP2B6*6 CYP2B6 CYP CYP3A4 3A5 40% (42) CYP3A4 CYP3A4 ( P450 3 A 4) (84) CYP3A5( P450 3 A 5 ) (85%-95%) (30%-50%) CYP3A5*3 (>30%vs50%) CYP3A5 CYP3A5*6 * 7 (85) CYP3A CYP3A5 CYP3A4 CYP3A5 1 10

11 CYP3A4 ( )CYP3A5 DNA 30 (4- ) ER 100 (86) (86) (87) (88) (89) (86) (16)(22) 1980 ER 4- (16) (16) (89) (90) ( 91) N- 4 CYP2D6 (15) CYP2D6 CYP2D6 2 (a) CYP2D6 (b) CYP2D6 2 CYP2D6 in vivo CYP2D6 (8)(11)(22) 11

12 Selective Serotonin Reuptake Inhibitors: SSRI CYP2D6 SSRI CYP2D6 CYP2D6 / CYP2D6 CYP2D6*4 PM (11) PM IM UM (8) CYP2D6 N- N- 1 (92) SULT1A1 CYP2D6 SULT1A1(sulfotransferase 1A 1) (32) CYP2D6 SULT1A1 SULT1A1 4 N- CYP2D6 CYP2D6 IM CYP2D6*10 4 (17) CYP2D6*10 4-hydroxytamoxifen (93) CYP2D6*10 IM IM CYP2D6 PM CYP2D6 ER III (North Central Cancer Treatment Group aduvant breast cancer trial) 12

13 CYP2D6*4 (94) CYP2D6 CYP2D6 (SSRI) (95) CYP2D6 ER (79) 71 PM IM ( CYP2D6*4 *5 *10 *41 ) (Figure 2) ER UM CYP2C19*17 *17 *17 CYP2D6*4 *5 *10 *41 50% CYP2D6 EM CYP2D6 CYP2C19 UM

14 2 CYP2D6 Metabolizer (RFT) Kaplan-Meier (A) (TAM) EM (PM IM) RFT (B)TAM CYP2D6 RFT [Schroth (79)] hetem ( EM) Schroth W :J Clin Oncol (33): c2008 American Society of Clinical oncology. All rights reserved CYP2D6 IM CYP2D6*10 *10 *10 (17) CYP2D6*10 (93) CYP2D6*10 CYP2D6 CYP2D6*10 10 (96) CYP2D6 CYP2D6 (97) CYP2D6*4 (98) CYP2D6 CYP2D6*4 (99) CYP2D6 Italian Tamoxifen Trail CYP2D6*4/*4 CYP2D6 (100) Women s Health Eating and Living 14

15 randomized trial (101) (78%) 12.9% % BRCA1(Breast Cancer 1( )) BRCA2(Breast Cancer 2( )) CYP2D6 PM (102) ER ER BRCA AIs ER (103) Markov CYP2D6 CYP2D6*4 BIG1-98 trial Trial Goets (94) AIs CYP2D6 CYP2D6 EM 5 AI : CYP2D6 CYP2D6 CYP2D6 CYP2D6 metabolizer CYP2D6 ER SSRIs CYP2D6 CYP2D6 CYP2D6 15

16 SSRIs SSRIs 1 (104) CYP2D6 CYP2D6 (11)(105) citalopram escitalopram SSRI venlafaxine CYP2D6 2 CYP2D6 CYP2D6 CYP2D6 Goetz (94) Schroth (79) PM CYP2D6*3 *4 *5 IM *41 *17 *10 (*9 ) IM (59) CYP2D6 ( vs AI) CYP2D6 EM EM CYP2D6 AI PM IM IM IM UM CYP2D6 ( 4-16

17 CYP2D6 ER CYP2D6 AI (107) ER (106) Metabolizer CYP2D6 Author Contributions All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data (b) drafting or revising the article for intellectual content and (c) final approval of the published article. Authors Disclosures of Potential Conflicts of Interest Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest 17

18 Employment or Leadership None declared. Consultant or Advisory Role None declared. Stock Ownership None declared. Honoraria None declared. Research Funding Robert Bosch Foundation, Stuttgart, Germany, and Bundesministerium für Bildung und Forschung Grant No. 01ZP0502. Expert Testimony None declared. Role of Sponsor The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript. 1 Nonstandard abbreviations ER, estrogen receptor CYP, cytochrome P450 UGT, UDP-glucuronosyltransferase SULT, sulfotransferase EM, extensive metabolizer PM, poor metabolizer IM, intermediate metabolizer UM, ultrarapid metabolizer SSRI, serotonin reuptake inhibitor AI, aromatase inhibitor. 2 Human genes CYP2D6, cytochrome P450, family 2, subfamily D, polypeptide 6 CYP2D7P1, cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 1 CYP2D7P2, cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene 2 CYP2D8P1, cytochrome P450, family 2, subfamily D, polypeptide 8 pseudogene 1 CYP2D8P2, cytochrome P450, family 2, subfamily D, polypeptide 8 pseudogene 2 CYP2C9, cytochrome P450, family 2, subfamily C, polypeptide 9 CYP2C19, cytochrome P450, family 2, subfamily C, polypeptide 19 CYP2B6, cytochrome P450, family 2, subfamily B, polypeptide 6 CYP3A4, cytochrome P450, family 2, subfamily A, polypeptide 4 CYP3A5, cytochrome P450, family 2, subfamily A, polypeptide 5 SULT1A1, sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1 BRCA1, breast cancer 1, early onset BRCA2, breast cancer 2, early onset. 18

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