5 research outputs found
Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling
The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes
The pregnane X receptor down-regulates organic cation transporter 1 (SLC22A1) in human hepatocytes by competing for (“squelching”) SRC-1 coactivator
International audienc
2‑(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists
Constitutive
androstane receptor (CAR) is a key regulator of xenobiotic
and endobiotic metabolism. Together with pregnane X (PXR) and aryl
hydrocarbon (AHR) receptors, it is referred to as “xenobiotic
receptor”. The unique properties of human CAR, such as its
high constitutive activity, both direct (ligand-binding domain-dependent)
and indirect activation have hindered the discovery of direct selective
human CAR ligands. Herein, we report a novel class of direct human
CAR agonists in a group of 2-(3-methoxyphenyl)quinazoline derivatives.
The compounds are even more potent activators of human CAR than is
prototype 6-(4-chlorophenyl)imidazo[2,1-<i>b</i>][1,3]thiazole-5-carbaldehyde <i>O</i>-(3,4-dichlorobenzyl)oxime (CITCO). The three most potent
ligands are at the same time extremely potent activators of the other
xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor,
which regulate major xenobiotic-metabolizing enzymes and efflux transporters.
Thus, the novel CAR ligands can be also considered as constituting
the first class of potent pan-xenobiotic receptor ligands that can
serve as potential antidotes boosting overall metabolic elimination
of xenobiotic or toxic compounds
2‑(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists
Constitutive
androstane receptor (CAR) is a key regulator of xenobiotic
and endobiotic metabolism. Together with pregnane X (PXR) and aryl
hydrocarbon (AHR) receptors, it is referred to as “xenobiotic
receptor”. The unique properties of human CAR, such as its
high constitutive activity, both direct (ligand-binding domain-dependent)
and indirect activation have hindered the discovery of direct selective
human CAR ligands. Herein, we report a novel class of direct human
CAR agonists in a group of 2-(3-methoxyphenyl)quinazoline derivatives.
The compounds are even more potent activators of human CAR than is
prototype 6-(4-chlorophenyl)imidazo[2,1-<i>b</i>][1,3]thiazole-5-carbaldehyde <i>O</i>-(3,4-dichlorobenzyl)oxime (CITCO). The three most potent
ligands are at the same time extremely potent activators of the other
xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor,
which regulate major xenobiotic-metabolizing enzymes and efflux transporters.
Thus, the novel CAR ligands can be also considered as constituting
the first class of potent pan-xenobiotic receptor ligands that can
serve as potential antidotes boosting overall metabolic elimination
of xenobiotic or toxic compounds