RT Journal Article
SR Electronic
T1 Natural Protein Variants of Pregnane X Receptor with Altered Transactivation Activity Toward <em>CYP3A4</em>
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1454
OP 1459
VO 29
IS 11
A1 Hustert, Elisabeth
A1 Zibat, Arne
A1 Presecan-Siedel, Elena
A1 Eiselt, Regina
A1 Mueller, Romy
A1 Fuß, Christine
A1 Brehm, Ilka
A1 Brinkmann, Ulrich
A1 Eichelbaum, Michel
A1 Wojnowski, Leszek
A1 Burk, Oliver
YR 2001
UL http://dmd.aspetjournals.org/content/29/11/1454.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics