title: Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2.
abstract: Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: J
authors: J
authors: Matthaei
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: M V
authors: MV
authors: Tzvetkov
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: J
authors: J
authors: Strube
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: D
authors: D
authors: Sehrt
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: C
authors: C
authors: Sachse-Seeboth
authors: Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
authors: J B
authors: JB
authors: Hjelmborg
authors: Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
authors: S
authors: S
authors: Möller
authors: Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
authors: U
authors: U
authors: Halekoh
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
authors: U
authors: U
authors: Hofmann
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.|Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
authors: M
authors: M
authors: Schwab
authors: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
authors: R
authors: R
authors: Kerb
authors: Institute for Clinical Pharmacology, University Medical Center, Göttingen, Georg-August University, Göttingen, Germany.
authors: J
authors: J
authors: Brockmöller
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002110:Caffeine / Q000378:metabolism*; D003278:Contraceptives, Oral, Hormonal / Q000008:administration & dosage; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004777:Environment; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012907:Smoking / Q000378:metabolism; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult
chemical_list: D003278:Contraceptives, Oral, Hormonal; D002110:Caffeine; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human