Increase in Urea in Conjunction with L-arginine Metabolism in the Liver Leads to Induction of Cytochrome P450 2E1 (CYP2E1): the Role of Urea in CYP2E1 Induction by Acute Renal Failure

A number of xenobiotics and certain pathophysiological situations cause the induction of CYP2E1. The present study was designed to establish the role of plasma urea nitrogen and L-arginine on hepatic CYP2E1 expression in rats or rats with acute renal failure. Exposure of rats to a single intravenous dose of 5 mg/kg uranyl nitrate caused renal failure in 5 days (ARF), as evidenced by increases in plasma urea nitrogen level and kidney to body weight ratio. Northern and Western blot analyses revealed that hepatic CYP2E1 was 2- to 4-fold induced by ARF. Treatment of rats with either 10% glucose in drinking water for 5 days following a single injection of uranyl nitrate or two injections of recombinant growth hormone (5 units/kg, s.c., twice a day) on the 4th day after uranyl nitrate injection reduced both the rise in plasma urea nitrogen and the induction of CYP2E1. Exposure of rats to urea (approximately 225 mg/kg/day) in drinking water for 1 to 3 day(s) resulted in significant increases in CYP2E1 mRNA and protein. Furthermore, perfusion of the liver with 25 mM urea for 24 h resulted in CYP2E1 induction with an increase in the mRNA. The levels of CYP2E1 protein and mRNA were increased in rats perfused with 25 mM L-arginine for 24 h (i.e., a 4-fold increase). Hence, L-arginine, which is irreversibly hydrolyzed to urea and ornithine by arginase, also induced hepatic CYP2E1. The results of the present study provided evidence that increases in plasma urea in conjunction with L-arginine metabolism lead to the induction of CYP2E1 in the liver.