PT - JOURNAL ARTICLE AU - Tomoya Yasujima AU - Kosuke Saito AU - Rick Moore AU - Masahiko Negishi TI - Phenobarbital and Insulin Reciprocate Activation of the Nuclear Receptor Constitutive Androstane Receptor through the Insulin Receptor AID - 10.1124/jpet.116.232140 DP - 2016 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 367--374 VI - 357 IP - 2 4099 - http://jpet.aspetjournals.org/content/357/2/367.short 4100 - http://jpet.aspetjournals.org/content/357/2/367.full SO - J Pharmacol Exp Ther2016 May 01; 357 AB - 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.