Cytochrome P450 monoxygenases (P450) are responsible for the metabolism and detoxification of many therapeutics. Induction of P450 enzymes by drugs can lead to potentially harmful drug-drug interactions and alterations in drug therapy efficacy. Drug induction of P450 enzymes has been shown to involve the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). Recently, we reported that the nuclear receptor CAR mediated phenytoin (DPH) induction of the murine Cyp2b10 and Cyp2c29 genes. Herein, we report the discovery of a second DPH inducible murine CYP2C, Cyp2c37. Quantitative RT-PCR and immunoblot data demonstrate that hepatic CYP2C37 mRNA and protein amounts are increased by DPH. We have identified a putative CAR response element (CAR-RE) at -2.8kb from the start of translation of the Cyp2c37 gene. Mutation of this CAR-RE in Cyp2c37 luciferase promoter constructs demonstrated that it is necessary for mCAR constitutive transactivation and that induction is governed by a transcriptional regulation mechanism. Furthermore in CAR-null mice, quantitative RT-PCR results indicate that the induction of CYP2C37 mRNA by DPH is abolished. These results suggest that DPH induction of the Cyp2c37 gene, like the Cyp2b10 and Cyp2c29 genes, is regulated by mCAR. However, in CAR-null mice induction of CYP3A11 mRNA is not abolished suggesting that both CAR and PXR can mediate DPH induction of P450 genes, depending on the gene promoter. This research was supported by the intramural division of the NIEHS.