Kurzfassung

The induction of xenobiotic-metabolizing enzymes and transporters in the liver constitutes a rapid, adaptive defense
against xenobiotics. The induction is mediated by the xenosensors pregnane X receptor (PXR, NR1I2) and
constitutive androstane receptor (CAR, NR1I3).
Our data show that CAR-mediated induction in response to the model CAR ligand TCPOBOP is transmitted to the
F1 offspring by female mice induced months prior to the mating. This effect is mediated by the transmission of the
lipophilic...The induction of xenobiotic-metabolizing enzymes and transporters in the liver constitutes a rapid, adaptive defense
against xenobiotics. The induction is mediated by the xenosensors pregnane X receptor (PXR, NR1I2) and
constitutive androstane receptor (CAR, NR1I3).
Our data show that CAR-mediated induction in response to the model CAR ligand TCPOBOP is transmitted to the
F1 offspring by female mice induced months prior to the mating. This effect is mediated by the transmission of the
lipophilic CAR ligand TCPOBOP via milk. F1 offspring exhibit decreased drug efficacy and alterations in the bone
and energy metabolism.
For two reasons, such transgenerational transmission of induction is even more likely to occur following the
activation of the other xenobiotic sensor, PXR. Firstly, the much larger ligand binding domain of PXR enables its
activation by numerous clinically relevant drugs such as anticonvulsives, statins, antidepressants, antiretrovirals,
antithrombotics, antibiotics, antimycotics, antituberculotics and herbal compounds. Secondly, PXR is the pivotal
activator of CYP3A4, which metabolizes, at least in part, 50% of currently prescribed drugs, including most of the
aforementioned PXR activators.
The purpose of this project is to prove that clinically relevant PXR ligands capable of form long-term depots in
adipose tissue cause multigenerational induction drug effects. The result would provide a basis for a DFG-funded
investigation of the PXR-mediated effects on drug metabolism and on endobiotic-related disturbances in the next
generation. This line of research may establish an entirely new class of adverse drug reactions, namely
multigenerational ones.» weiterlesen» einklappen