Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neurosciences, Lausanne University Hospital, Prilly, Lausanne, Switzerland.
Pharmacogenet Genomics. 2013 May;23(5):286-92. doi: 10.1097/FPC.0b013e3283602e75.
There is a high interindividual variability in cytochrome P4501A2 (CYP1A2) activity and in its inducibility by smoking, only poorly explained by known CYP1A2 polymorphisms. We aimed to study the contribution of other regulatory pathways, including transcription factors and nuclear receptors, toward this variability.
CYP1A2 activity was determined by the paraxanthine/caffeine ratio in 184 smokers and in 113 of them who were abstinent for 4 weeks. Participants were genotyped for 22 polymorphisms in 12 genes.
A significant influence on CYP1A2 inducibility was observed for the NR1I3 rs2502815 (P=0.0026), rs4073054 (P=0.029), NR2B1 rs3818740 (P=0.0045), rs3132297 (P=0.036), AhR rs2282885 (P=0.040), rs2066853 (P=0.019), NR1I1 rs2228570 (P=0.037), and NR1I2 rs1523130 (P=0.044) polymorphisms. Among these, the NR1I3 rs2502815 (P=0.0045), rs4073054 (P=0.048), and NR2B1 rs3818740 (P=0.031) also influenced CYP1A2 basal activity.
This is the first in-vivo demonstration of the influence of genes involved in CYP1A2 regulatory pathways on its basal activity and inducibility by smoking. These results need to be confirmed by other studies.
细胞色素 P4501A2（CYP1A2）的活性及其对吸烟的诱导作用在个体间存在很大差异，这仅能用已知的 CYP1A2 多态性来部分解释。我们旨在研究其他调节途径，包括转录因子和核受体，对这种变异性的贡献。
通过对 184 名吸烟者和其中 113 名戒烟 4 周的吸烟者的对黄嘌呤/咖啡因比值，来测定 CYP1A2 活性。参与者对 12 个基因中的 22 个多态性进行了基因分型。
NR1I3 rs2502815（P=0.0026）、rs4073054（P=0.029）、NR2B1 rs3818740（P=0.0045）、rs3132297（P=0.036）、AhR rs2282885（P=0.040）、rs2066853（P=0.019）、NR1I1 rs2228570（P=0.037）和 NR1I2 rs1523130（P=0.044）多态性对 CYP1A2 的诱导作用有显著影响。在这些多态性中，NR1I3 rs2502815（P=0.0045）、rs4073054（P=0.048）和 NR2B1 rs3818740（P=0.031）也影响 CYP1A2 的基础活性。
这是首次在体内证明参与 CYP1A2 调节途径的基因对其基础活性和吸烟诱导作用的影响。这些结果需要其他研究来证实。
