title: Phenobarbital and Insulin Reciprocate Activation of the Nuclear Receptor Constitutive Androstane Receptor through the Insulin Receptor.
abstract: Phenobarbital (PB) antagonized insulin to inactivate the insulin receptor and attenuated the insulin receptor downstream protein kinase B (AKT)-forkhead box protein O1 and extracellular signal-regulated kinase 1/2 signals in mouse primary hepatocytes and HepG2 cells. Hepatic AKT began dephosphorylation in an early stage of PB treatment, and blood glucose levels transiently increased in both wild-type and constitutive androstane receptor (CAR) knockout (KO) mice. On the other hand, blood glucose levels increased in wild-type mice, but not KO mice, in later stages of PB treatment. As a result, PB, acting as an insulin receptor antagonist, elicited CAR-independent increases and CAR-dependent decreases of blood glucose levels at these different stages of treatment, respectively. Reciprocally, insulin activation of the insulin receptor repressed CAR activation and induction of its target CYP2B6 gene in HepG2 cells. Thus, PB and insulin cross-talk through the insulin receptor to regulate glucose and drug metabolism reciprocally.
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yasujima
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Rick
authors.initials: R
authors.lastname: Moore
authors.affiliation: Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina negishi@niehs.nih.gov.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000187:drug effects; D000072467:Cytochrome P450 Family 2; D022781:Hepatocytes / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010634:Phenobarbital / Q000494:pharmacology*; D020239:Receptor Cross-Talk / Q000187:drug effects; D011972:Receptor, Insulin / Q000187:drug effects*; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D013250:Steroid Hydroxylases / Q000378:metabolism; D014162:Transfection
chemical_list: D001786:Blood Glucose; C577923:CASR protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D011972:Receptor, Insulin; D010634:Phenobarbital