Toxicological Sciences 60, 11-19 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Cytochrome P450-Dependent Metabolism of Trichloroethylene in Rat Kidney
* Department of Pharmacology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, Michigan 48201; and
National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC 20460
The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite consistently detected and was used as a measurement of P450-dependent metabolism of Tri. Pretreatment of rats with pyridine increased CH formation in both liver and kidney microsomes, whereas pretreatment of rats with clofibrate increased CH formation only in kidney microsomes. Pyridine increased CYP2E1 expression in both liver and kidney microsomes, whereas clofibrate had no effect on hepatic but increased renal CYP2E1 and CYP2C11 protein levels. These results suggest a role for CYP2E1 in both the hepatic and renal metabolism of Tri and a role for CYP2C11 in the renal metabolism of Tri. Studies with the general P450 inhibitor SKF-525A and the CYP2E1 competitive substrate chlorzoxazone provided additional support for the role of CYP2E1 in both tissues. CH formation was higher in PT cells than in DT cells and was time and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent. However, pretreatment of rats with either pyridine or clofibrate had no effect on CYP2E1 or CYP2C11 protein levels or on CH formation in isolated cells. These data show for the first time that Tri can be metabolized to at least one of its P450 metabolites in the kidneys and quantitate the effect of P450 induction on Tri metabolism in the rat kidney.
Key Words: trichloroethylene; kidney; metabolism; cytochrome P450; proximal tubular cells; enzyme induction.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. A. Lock and C. J. Reed Trichloroethylene: Mechanisms of Renal Toxicity and Renal Cancer and Relevance to Risk Assessment Toxicol. Sci., June 1, 2006; 91(2): 313 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-G. Forkert, B. Millen, L. H. Lash, D. A. Putt, and B. I. Ghanayem Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 520 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-G. Forkert, R. M. Baldwin, B. Millen, L. H. Lash, D. A. Putt, M. A. Shultz, and K. S. Collins PULMONARY BIOACTIVATION OF TRICHLOROETHYLENE TO CHLORAL HYDRATE: RELATIVE CONTRIBUTIONS OF CYP2E1, CYP2F, AND CYP2B1 Drug Metab. Dispos., October 1, 2005; 33(10): 1429 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. DuTeaux, T. Berger, R. A. Hess, B. L. Sartini, and M. G. Miller Male Reproductive Toxicity of Trichloroethylene: Sperm Protein Oxidation and Decreased Fertilizing Ability Biol Reprod, May 1, 2004; 70(5): 1518 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Keys, J. V. Bruckner, S. Muralidhara, and J. W. Fisher Tissue Dosimetry Expansion and Cross-Validation of Rat and Mouse Physiologically Based Pharmacokinetic Models for Trichloroethylene Toxicol. Sci., November 1, 2003; 76(1): 35 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Lash and J. C. Parker Hepatic and Renal Toxicities Associated with Perchloroethylene Pharmacol. Rev., May 11, 2001; (2001) 2. [Abstract] [Full Text]
|
|
|
|
|
|
L. H. Lash and J. C. Parker Hepatic and Renal Toxicities Associated with Perchloroethylene Pharmacol. Rev., June 1, 2001; 53(2): 177 - 208. [Abstract] [Full Text] [PDF]
|
|