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Title: Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles

Abstract

The human cytochrome P450 3A (CYP3A) enzymes, which metabolize 50% of currently used therapeutic drugs, exhibit great interindividual differences in activity that have a major impact on drug treatment outcome, but hitherto no genetic background importantly contributing to this variation has been identified. In this study we show that CYP3A4 mRNA and hnRNA contents with a few exceptions vary in parallel in human liver, suggesting that mechanisms affecting CYP3A4 transcription, such as promoter polymorphisms, are relevant for interindividual differences in CYP3A4 expression. Tanzanian (n = 143) healthy volunteers were phenotyped using quinine as a CYP3A probe and the results were used for association studies with CYP3A4 genotypes. Carriers of CYP3A4*1B had a significantly lower activity than those with CYP3A4*1 whereas no differences were seen for five other SNPs investigated. Nuclear proteins from the B16A2 hepatoma cells were found to bind with less affinity to the CYP3A4*1B element around -392 bp as compared to CYP3A4*1. The data indicate the existence of a genetic CYP3A4 polymorphism with functional importance for interindividual differences in enzyme expression.

Authors:
 [1];  [2];  [3];  [3];  [1]
  1. Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden)
  2. Department of Clinical Pharmacology, Faculty of Medicine, Muhimbili University College of Health Sciences, Dar es Salaam (Tanzania)
  3. Division of Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology, Karolinska Institutet and Hospital Pharmacy, Huddinge University Hospital, Stockholm (Sweden)
Publication Date:
OSTI Identifier:
20793198
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 338; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2005.09.020; PII: S0006-291X(05)02019-X; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARRIERS; ENZYMES; GENOTYPE; HEPATOMAS; LIVER; PHENOTYPE; PROMOTERS; QUININE; TRANSCRIPTION

Citation Formats

Rodriguez-Antona, Cristina, Sayi, Jane G, Gustafsson, Lars L, Bertilsson, Leif, and Ingelman-Sundberg, Magnus. Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. United States: N. p., 2005. Web. doi:10.1016/J.BBRC.2005.0.
Rodriguez-Antona, Cristina, Sayi, Jane G, Gustafsson, Lars L, Bertilsson, Leif, & Ingelman-Sundberg, Magnus. Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles. United States. https://doi.org/10.1016/J.BBRC.2005.0
Rodriguez-Antona, Cristina, Sayi, Jane G, Gustafsson, Lars L, Bertilsson, Leif, and Ingelman-Sundberg, Magnus. 2005. "Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles". United States. https://doi.org/10.1016/J.BBRC.2005.0.
@article{osti_20793198,
title = {Phenotype-genotype variability in the human CYP3A locus as assessed by the probe drug quinine and analyses of variant CYP3A4 alleles},
author = {Rodriguez-Antona, Cristina and Sayi, Jane G and Gustafsson, Lars L and Bertilsson, Leif and Ingelman-Sundberg, Magnus},
abstractNote = {The human cytochrome P450 3A (CYP3A) enzymes, which metabolize 50% of currently used therapeutic drugs, exhibit great interindividual differences in activity that have a major impact on drug treatment outcome, but hitherto no genetic background importantly contributing to this variation has been identified. In this study we show that CYP3A4 mRNA and hnRNA contents with a few exceptions vary in parallel in human liver, suggesting that mechanisms affecting CYP3A4 transcription, such as promoter polymorphisms, are relevant for interindividual differences in CYP3A4 expression. Tanzanian (n = 143) healthy volunteers were phenotyped using quinine as a CYP3A probe and the results were used for association studies with CYP3A4 genotypes. Carriers of CYP3A4*1B had a significantly lower activity than those with CYP3A4*1 whereas no differences were seen for five other SNPs investigated. Nuclear proteins from the B16A2 hepatoma cells were found to bind with less affinity to the CYP3A4*1B element around -392 bp as compared to CYP3A4*1. The data indicate the existence of a genetic CYP3A4 polymorphism with functional importance for interindividual differences in enzyme expression.},
doi = {10.1016/J.BBRC.2005.0},
url = {https://www.osti.gov/biblio/20793198}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 1,
volume = 338,
place = {United States},
year = {Fri Dec 09 00:00:00 EST 2005},
month = {Fri Dec 09 00:00:00 EST 2005}
}