title: 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.
abstract: 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.
authors.affiliation: National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, South Korea.
authors.forename: Hye Chin
authors.initials: HC
authors.lastname: Chung
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Myung Gull
authors.initials: MG
authors.lastname: Lee
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism* / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004790:Enzyme Induction; D005947:Glucose / Q000494:pharmacology; D019382:Human Growth Hormone / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019382:Human Growth Hormone; D014508:Urea; D001120:Arginine; D019392:Cytochrome P-450 CYP2E1; D005947:Glucose