Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden.
Pharmacogenet Genomics. 2013 May;23(5):279-85. doi: 10.1097/FPC.0b013e3283602876.
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.
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.
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.
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.
非典型抗精神病药奥氮平（OLA）的代谢部分由细胞色素 P450（CYP）1A2 催化，而 CYP1A2 是芳烃受体（AHR）介导诱导的靶标。我们研究了四个顺式作用多态性（CYP1A1 和 CYP1A2 基因座之间的 rs2470893C>T 和 rs2472297C>T，以及 CYP1A2 内的 rs762551C>A 和 rs2472304A>G）以及 AHR 基因座上游的一个反式作用多态性（rs4410790C>T）对个体间系统 OLA 暴露的影响。
使用 Illumina GoldenGate 测定法对 342 名接受长期 OLA 治疗的白种人精神科患者进行基因分型。根据 OLA 和 4'-去甲基 OLA（DMO）与 OLA 的比值（C/Ds）的剂量调整稳态血清浓度，评估单倍型和基因型的影响，这是 CYP1A2 介导的 OLA 代谢的标志物。
CYP1A 单倍型[rs2470893（T）-rs2472297（T）-rs762551（A）]与 DMO/OLA 比值增加和 OLA C/Ds 降低相关。该单倍型不能被 rs762551（A）标记，但可以被 rs2472297C>T 标记，这是一种进一步被确定为 DMO/OLA 比值（P=0.0001）和 OLA C/D（P=0.01）的显著协变量的单核苷酸多态性。AHR rs4410790C>T 仅影响 DMO/OLA 比值（P=0.02）。在不吸烟者中，携带 rs2472297（T）并纯合 rs4410790（C）[n=26；平均值=0.22，95%置信区间（CI）0.19-0.26]的患者与携带 rs4410790（T）和纯合 rs2472297（C）的患者相比，DMO/OLA 比值高出 1.7 倍[n=50；平均值=0.13，95%CI 0.12-0.16，P=0.0001]，OLA C/D 无显著降低。
报告的 CYP1A2*1F（也称为 CYP1A2-163A，rs762551C>A）对系统 OLA 暴露的影响无法得到验证。CYP1A1/CYP1A2 rs2472297C>T 和 AHR rs4410790C>T 可能是与 CYP1A2 介导的代谢变异性相关的有用遗传标记，但对系统 OLA 暴露的定量影响较小。
