title: Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR) or peroxisome proliferator-activated receptor α (PPARα) is enhanced by pregnane X receptor (PXR) activation in mice.
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.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Shizu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Benoki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Numakura
authors.forename: Susumu
authors.initials: S
authors.lastname: Kodama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D000090702:Constitutive Androstane Receptor; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D011725:Pyridines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D011285:Pregnenolone Carbonitrile; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; C006253:pirinixic acid; D010634:Phenobarbital