Vol. 30, Issue 6, 739-746, June 2002

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

Hye Chin Chung, So Hee Kim, Myung Gull Lee, and Sang Geon Kim

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University (H.C.C., M.G.L., S.G.K.); and College of Dentistry, Kangnung National University, South Korea (S.H.K)

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 (~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.