Abstract
Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR), constitutive active/androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα) play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPARα activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) and phenobarbital, or PPARα activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16α-carbonitrile (PCN) alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPARα is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics.
Highlights
Xenobiotic-sensing pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are members of the NR1I subfamily of the nuclear receptor gene superfamily
In our preliminary experiments, using a quantitative reverse transcription-PCR (RT-PCR) analysis, we found that hepatic mRNA levels of some cell cycle-associated genes including Foxm1 and Ccnd1 (Cyclin D1) were increased in mice by treatment with the murine CAR ligand 1,4-bis[(3,5dichloropyridin-2-yl)oxy]benzene (TCPOBOP) but not with pregnenolone 16a-carbonitrile (PCN) (Yoshinari et al unpublished results)
We have investigated the influence of PXR activation on hepatocyte proliferation and the role of PXR in the xenobioticinduced hepatocyte proliferation mediated by CAR or peroxisome proliferator-activated receptor a (PPARa) in mice
Summary
Xenobiotic-sensing pregnane X receptor (PXR, NR1I2) and constitutive active/androstane receptor (CAR, NR1I3) are members of the NR1I subfamily of the nuclear receptor gene superfamily Both receptors play pivotal roles in the xenobioticinduced expression of genes encoding drug-metabolizing enzymes and transporters, such as CYP3As and CYP2Bs, UDP-glucoronosyltransferases, sulfotransferases, glutathione-S-transferases, and ATP-binding cassette transporters [1,2,3]. CAR has been reported to promote hepatocarcinogenesis in response to xenobiotics in mice through inducing cell proliferation and suppressing apoptosis without DNA lesions (see below). It remains unclear whether PXR has such functions despite the functional similarities with CAR
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