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Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure.
Pharmacogenet Genomics. 2013 May; 23(5):279-85.PG

Abstract

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.

Authors+Show Affiliations

Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23492908

Citation

Söderberg, Mao M., et al. "Influence of CYP1A1/CYP1A2 and AHR Polymorphisms On Systemic Olanzapine Exposure." Pharmacogenetics and Genomics, vol. 23, no. 5, 2013, pp. 279-85.
Söderberg MM, Haslemo T, Molden E, et al. Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure. Pharmacogenet Genomics. 2013;23(5):279-85.
Söderberg, M. M., Haslemo, T., Molden, E., & Dahl, M. L. (2013). Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure. Pharmacogenetics and Genomics, 23(5), 279-85. https://doi.org/10.1097/FPC.0b013e3283602876
Söderberg MM, et al. Influence of CYP1A1/CYP1A2 and AHR Polymorphisms On Systemic Olanzapine Exposure. Pharmacogenet Genomics. 2013;23(5):279-85. PubMed PMID: 23492908.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of CYP1A1/CYP1A2 and AHR polymorphisms on systemic olanzapine exposure. AU - Söderberg,Mao M, AU - Haslemo,Tore, AU - Molden,Espen, AU - Dahl,Marja-Liisa, PY - 2013/3/16/entrez PY - 2013/3/16/pubmed PY - 2013/9/11/medline SP - 279 EP - 85 JF - Pharmacogenetics and genomics JO - Pharmacogenet. Genomics VL - 23 IS - 5 N2 - 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. SN - 1744-6880 UR - https://www.unboundmedicine.com/medline/citation/23492908/Influence_of_CYP1A1/CYP1A2_and_AHR_polymorphisms_on_systemic_olanzapine_exposure_ L2 - http://dx.doi.org/10.1097/FPC.0b013e3283602876 DB - PRIME DP - Unbound Medicine ER -