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Session 1: Cell death Poster 16
Involvement of AMPK signaling in liver xenobiotic-metabolizing enzymes regulation.
Brice SID, Nicolas DEJEAN, Christophe GLORIEUX, Raphael BECK, Julien
VERRAX and Pedro Buc CALDERON
Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute,
Université catholique de Louvain, 1200-Brussels. BELGIUM. Email:
brice.sid@uclouvain.be
AMP-activated protein kinase (AMPK) is a phylogenetically conserved serine/threonine
protein kinase, which has been proposed as a metabolic master switch mediating the cellular
adaption to environmental or nutritional stress factors. AMPK responds to any cellular stress
that threatens to lower ATP levels by arresting nonessential ATP-using functions and
stimulating ATP-generating pathways. Cytochrome P450 (CYPs) and Transferases are
responsible for metabolism of most xenobiotics and required for the efficient elimination of
foreign chemicals from the body. Paradoxically, theses enzymes may activate biologically
inert compounds to eletrophilic derivatives that can cause toxicity, cell death and sometimes
cellular transformation resulting in cancer. Because the regulation of theses enzymes can be
affected by metabolic and nutritional stress and some studies showed that AMPK is involved
in the induction of some CYPs in human hepatoma-derived cells and in primary cultures of
human and mouse hepatocytes, we investigated the role of AMPK in rat liver xenobiotic
metabolism regulation. In our study, we used rat precision-cut liver slices (PCLS), which are
described as valuable tools for in vitro metabolic studies of drug candidates. As compared to
isolated hepatocytes, this model offers the advantages of preserving the tissue architecture and
the proportion of the different cell types. We showed that treatment of the slices with
A769662 AMPK activator during 6h induces AMPK phosphorylation on Thr172 residue,
which is essential for its activity as well as downstream Ser79 phosphorylation of acetyl-
CoA-carboxylase (ACC), a metabolic target of AMPK. In parallel, A769662 treatment
significantly decreases CYP2E1 and glucuronosyltransferases (UGT) activities without
altering ATP content and lactate deshydrogenase leakage. These data suggest an essential role
of AMPK in the liver xenobiotic metabolism regulation.
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