{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T22:06:03Z","timestamp":1770501963778,"version":"3.49.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":3349,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Phenobarbital is a lipophilic molecule used as a sedative and antiepileptic drug that elicits a multitude of effects in the liver, including gross liver enlargement, hepatocyte hypertrophy, and induced expression of drug-metabolizing enzymes and other liver-specific genes. The constitutive androstane receptor (CAR; NR1I3) and to a lesser extent the pregnane X receptor (PXR; NR1I2) are responsible for mediating induction of many phenobarbital-responsive genes. However, CAR-mediated transcriptional control of some genes is critically dependent on hepatocyte nuclear factor 4 alpha (HNF-4\u03b1; NR2A1), which itself regulates multiple liver-specific genes involved in hepatic growth, metabolism, and differentiation. We studied the effects of phenobarbital on HNF-4\u03b1 expression in hepatocytes and provide evidence that HNF-4\u03b1 nuclear expression is regulated in response to phenobarbital. Real-time polymerase chain reaction analyses revealed that HNF-4\u03b1 mRNA is modestly up-regulated by phenobarbital. In addition, nuclear expression of HNF-4\u03b1 protein is significantly elevated 3 hours after the administration of phenobarbital in wild-type, CAR\u2212\/\u2212, and CAR\u2212\/\u2212\/PXR\u2212\/\u2212 mice.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>analysis revealed that phenobarbital-induced HNF-4\u03b1 expression is both time- and dose dependent. In addition, the phosphatase inhibitor okadaic acid and the Ca2+\/calmodulin-dependent protein kinase II inhibitor KN62 block nuclear induction of HNF-4\u03b1 by phenobarbital. Furthermore, HNF-4\u03b1 nuclear expression is enhanced by inhibition of cyclic AMP\u2013dependent protein kinase A.<\/jats:bold>\n                                 <jats:bold>\n                                    In conclusion\n                                 <\/jats:bold>\n                                 <jats:bold>, induced nuclear expression of HNF-4\u03b1 and CAR is an integral part of the phenobarbital response, aimed at coordinated regulation of genes involved in drug metabolism and detoxification as well as maintenance of liver function.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.21234","type":"journal-article","created":{"date-parts":[[2006,6,27]],"date-time":"2006-06-27T07:26:57Z","timestamp":1151393217000},"page":"186-194","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":33,"title":["Phenobarbital regulates nuclear expression of HNF-4\u03b1 in mouse and rat hepatocytes independent of CAR and PXR"],"prefix":"10.1097","volume":"44","author":[{"given":"Aaron W.","family":"Bell","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George K.","family":"Michalopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-24-20241201","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1083\/jcb.25.3.627","article-title":"Phenobarbitalinduced synthesis of the microsomal drugmetabolizing enzyme system and its relationship to the proliferation of endoplasmic membranes. 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