OBJECTIVE: Metabolism of the atypical antipsychotic olanzapine (OLA) is partially catalyzed by cytochrome P450 (CYP) 1A2, a target of aryl hydrocarbon receptor (AHR)-mediated induction. We investigated the influence of four cis-acting polymorphisms (rs2470893C>T and rs2472297C>T between CYP1A1 and CYP1A2 loci, and rs762551C>A and rs2472304A>G within CYP1A2) as well as one trans-acting polymorphism upstream of the AHR locus (rs4410790C>T) on interindividual variation in systemic OLA exposure. METHODS: A cohort of 342 Caucasian psychiatric patients on long-term OLA treatment was genotyped using Illumina GoldenGate assays. The influence of haplotype and genotype was evaluated in terms of dose-adjusted steady-state serum concentrations (C/Ds) of OLA and the 4'-desmethyl OLA (DMO) to OLA ratio, a marker for CYP1A2-mediated metabolism of OLA. RESULTS: The CYP1A haplotype [rs2470893 (T)-rs2472297 (T)-rs762551 (A)] was associated with an increased DMO/OLA ratio and decreased C/Ds of OLA. This haplotype could not be tagged by rs762551 (A) but was tagged by rs2472297C>T, a single nucleotide polymorphism further identified as a significant covariate of the DMO/OLA ratio (P=0.0001) and OLA C/D (P=0.01). AHR rs4410790C>T influenced only the DMO/OLA ratio (P=0.02). Among nonsmokers, patients carrying rs2472297 (T) and homozygous for rs4410790 (C) [n=26; mean=0.22, 95% confidence interval (CI) 0.19-0.26] showed a 1.7-fold higher mean DMO/OLA ratio compared with those carrying rs4410790 (T) and homozygous for rs2472297 (C) (n=50; mean=0.13, 95% CI 0.12-0.16, P=0.0001), together with a nonsignificant decrease in the mean OLA C/D. CONCLUSION: The reported influence of CYP1A2*1F (also known as CYP1A2-163A, rs762551C>A) on systemic OLA exposure could not be verified. CYP1A1/CYP1A2 rs2472297C>T and AHR rs4410790C>T are potentially useful genetic markers associated with variability in CYP1A2-mediated metabolism, but are of minor quantitative importance for systemic OLA exposure.
OBJECTIVE: Metabolism of the atypical antipsychotic olanzapine (OLA) is partially catalyzed by cytochrome P450 (CYP) 1A2, a target of aryl hydrocarbon receptor (AHR)-mediated induction. We investigated the influence of four cis-acting polymorphisms (rs2470893C>T and rs2472297C>T between CYP1A1 and CYP1A2 loci, and rs762551C>A and rs2472304A>G within CYP1A2) as well as one trans-acting polymorphism upstream of the AHR locus (rs4410790C>T) on interindividual variation in systemic OLA exposure. METHODS: A cohort of 342 Caucasian psychiatricpatients on long-term OLA treatment was genotyped using Illumina GoldenGate assays. The influence of haplotype and genotype was evaluated in terms of dose-adjusted steady-state serum concentrations (C/Ds) of OLA and the 4'-desmethyl OLA (DMO) to OLA ratio, a marker for CYP1A2-mediated metabolism of OLA. RESULTS: The CYP1A haplotype [rs2470893 (T)-rs2472297 (T)-rs762551 (A)] was associated with an increased DMO/OLA ratio and decreased C/Ds of OLA. This haplotype could not be tagged by rs762551 (A) but was tagged by rs2472297C>T, a single nucleotide polymorphism further identified as a significant covariate of the DMO/OLA ratio (P=0.0001) and OLA C/D (P=0.01). AHR rs4410790C>T influenced only the DMO/OLA ratio (P=0.02). Among nonsmokers, patients carrying rs2472297 (T) and homozygous for rs4410790 (C) [n=26; mean=0.22, 95% confidence interval (CI) 0.19-0.26] showed a 1.7-fold higher mean DMO/OLA ratio compared with those carrying rs4410790 (T) and homozygous for rs2472297 (C) (n=50; mean=0.13, 95% CI 0.12-0.16, P=0.0001), together with a nonsignificant decrease in the mean OLA C/D. CONCLUSION: The reported influence of CYP1A2*1F (also known as CYP1A2-163A, rs762551C>A) on systemic OLA exposure could not be verified. CYP1A1/CYP1A2 rs2472297C>T and AHR rs4410790C>T are potentially useful genetic markers associated with variability in CYP1A2-mediated metabolism, but are of minor quantitative importance for systemic OLA exposure.
Authors: Enda M Byrne; Tõnu Esko; Michael A Nalls; Marilyn C Cornelis; Andrea Ganna; Nina Paynter; Keri L Monda; Najaf Amin; Krista Fischer; Frida Renstrom; Julius S Ngwa; Ville Huikari; Alana Cavadino; Ilja M Nolte; Alexander Teumer; Kai Yu; Pedro Marques-Vidal; Rajesh Rawal; Ani Manichaikul; Mary K Wojczynski; Jacqueline M Vink; Jing Hua Zhao; George Burlutsky; Jari Lahti; Vera Mikkilä; Rozenn N Lemaitre; Joel Eriksson; Solomon K Musani; Toshiko Tanaka; Frank Geller; Jian'an Luan; Jennie Hui; Reedik Mägi; Maria Dimitriou; Melissa E Garcia; Weang-Kee Ho; Margaret J Wright; Lynda M Rose; Patrik Ke Magnusson; Nancy L Pedersen; David Couper; Ben A Oostra; Albert Hofman; Mohammad Arfan Ikram; Henning W Tiemeier; Andre G Uitterlinden; Frank Ja van Rooij; Inês Barroso; Ingegerd Johansson; Luting Xue; Marika Kaakinen; Lili Milani; Chris Power; Harold Snieder; Ronald P Stolk; Sebastian E Baumeister; Reiner Biffar; Fangyi Gu; François Bastardot; Zoltán Kutalik; David R Jacobs; Nita G Forouhi; Evelin Mihailov; Lars Lind; Cecilia Lindgren; Karl Michaëlsson; Andrew Morris; Majken Jensen; Kay-Tee Khaw; Robert N Luben; Jie Jin Wang; Satu Männistö; Mia-Maria Perälä; Mika Kähönen; Terho Lehtimäki; Jorma Viikari; Dariush Mozaffarian; Kenneth Mukamal; Bruce M Psaty; Angela Döring; Andrew C Heath; Grant W Montgomery; Norbert Dahmen; Teresa Carithers; Katherine L Tucker; Luigi Ferrucci; Heather A Boyd; Mads Melbye; Jorien L Treur; Dan Mellström; Jouke Jan Hottenga; Inga Prokopenko; Anke Tönjes; Panos Deloukas; Stavroula Kanoni; Mattias Lorentzon; Denise K Houston; Yongmei Liu; John Danesh; Asif Rasheed; Marc A Mason; Alan B Zonderman; Lude Franke; Bruce S Kristal; Juha Karjalainen; Danielle R Reed; Harm-Jan Westra; Michele K Evans; Danish Saleheen; Tamara B Harris; George Dedoussis; Gary Curhan; Michael Stumvoll; John Beilby; Louis R Pasquale; Bjarke Feenstra; Stefania Bandinelli; Jose M Ordovas; Andrew T Chan; Ulrike Peters; Claes Ohlsson; Christian Gieger; Nicholas G Martin; Melanie Waldenberger; David S Siscovick; Olli Raitakari; Johan G Eriksson; Paul Mitchell; David J Hunter; Peter Kraft; Eric B Rimm; Dorret I Boomsma; Ingrid B Borecki; Ruth Jf Loos; Nicholas J Wareham; Peter Vollenweider; Neil Caporaso; Hans Jörgen Grabe; Marian L Neuhouser; Bruce Hr Wolffenbuttel; Frank B Hu; Elina Hyppönen; Marjo-Riitta Järvelin; L Adrienne Cupples; Paul W Franks; Paul M Ridker; Cornelia M van Duijn; Gerardo Heiss; Andres Metspalu; Kari E North; Erik Ingelsson; Jennifer A Nettleton; Rob M van Dam; Daniel I Chasman Journal: Mol Psychiatry Date: 2014-10-07 Impact factor: 15.992