Istrate, Monica Adina:
ISBN 9783899596427

Analysis of molecular mechanisms of the interindividual variability of CYP3A4 induction by rifampin # Pb., 130 S., 16 Abb., 14 Tab.

SCHLAGWORTE:
Gene
RegulationNuclear
Receptors

CYP3A4 is the most important human drug-metabolizing cytochrome P450 enzyme. It plays major roles in the phase I drug metabolism pathway. CYP3A4 is highly expressed in the human liver and intestine and is involved in the metabolism of more than 50% of all known therapeutic drugs. CYP3A4 expression in the liver varies up to 60-fold between individuals, which is a likely cause of variable drug response. A large part of the interindividual variability of CYP3A4 expression arises from induction of gene expression, which displays large interindividual variability. The causes of the interindividual variability of CYP3A4 induction are largely unknown. The induction of CYP3A4 is mediated by the nuclear receptor PXR, which upon activation by rifampin, binds to the proximal ER6 and distal DR3 (XREM) motifs within the CYP3A4 regulatory region. Nuclear receptors exhibit promiscuity with respect to DNA binding, supporting the idea of a competition for these binding sites. To understand the causes of the interindividual variability of CYP3A4 induction, the impact of nuclear receptors on human CYP3A4 expression and induction by rifampin in primary human hepatocytes was investigated.

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