title: Pharmacogenetics of CYP1A2 activity and inducibility in smokers and exsmokers.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Centre for Psychiatric Neurosciences, Lausanne University Hospital, Prilly, Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Dobrinas
authors.forename: Jacques
authors.initials: J
authors.lastname: Cornuz
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D000328:Adult; D002110:Caffeine / Q000008:administration & dosage; D000090702:Constitutive Androstane Receptor; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012907:Smoking / Q000235:genetics* / Q000473:pathology
chemical_list: D000090702:Constitutive Androstane Receptor; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D002110:Caffeine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2