title: Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4.
abstract: Between 45 and 60% of all drugs currently used are metabolized by the CYP3A4 protein. CYP3A4 expression in liver varies up to 60-fold in the general population, which can lead to ineffective drug therapy (high CYP3A4) or, on the other hand, to harmful drug reactions (low CYP3A4). Most of this variability has been attributed to genetic factors, but to date their identity remains unknown. Recently, it was shown that CYP3A expression is largely controlled by the pregnane X receptor (PXR). We, therefore, hypothesized that polymorphisms in PXR may contribute to CYP3A4 variability. The presence of PXR variants was investigated in two ethnic groups, Caucasians and Africans. Six missense mutations leading to variant PXR proteins were identified, and their consequences on CYP3A4 expression were analyzed. Expressed in LS174T cells, three protein variants, V140M, D163G, and A370T, exhibited altered basal and/or induced transactivation of CYP3A promoter reporter genes. Thus, these natural PXR protein variants may play a role in the observed interindividual variability of CYP3A4 expression and may be involved in rare, atypical responses to drugs or altered sensitivities to carcinogens.
authors.affiliation: EPIDAUROS Biotechnologie AG, Bernried, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Hustert
authors.forename: A
authors.initials: A
authors.lastname: Zibat
authors.forename: E
authors.initials: E
authors.lastname: Presecan-Siedel
authors.forename: R
authors.initials: R
authors.lastname: Eiselt
authors.forename: R
authors.initials: R
authors.lastname: Mueller
authors.forename: C
authors.initials: C
authors.lastname: Fuss
authors.forename: I
authors.initials: I
authors.lastname: Brehm
authors.forename: U
authors.initials: U
authors.lastname: Brinkmann
authors.forename: M
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: L
authors.initials: L
authors.lastname: Wojnowski
authors.forename: O
authors.initials: O
authors.lastname: Burk
mesh_terms: D044383:Black People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D008099:Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D000077297:Pregnane X Receptor; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics
chemical_list: D000077297:Pregnane X Receptor; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015534:Trans-Activators; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human