This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lim, C. E.L. Articles by Board, P. G. Search for Related Content PubMed PubMed Citation Articles by Lim, C. E.L. Articles by Board, P. G.

(American Journal of Pathology. 2004;165:679-693.)
© 2004 American Society for Investigative Pathology

Animal Models

Mice Deficient in Glutathione Transferase Zeta/Maleylacetoacetate Isomerase Exhibit a Range of Pathological Changes and Elevated Expression of Alpha, Mu, and Pi Class Glutathione Transferases

Cindy E.L. Lim^*, Klaus I. Matthaei^*, Anneke C. Blackburn^*, Richard P. Davis^*, Jane E. Dahlstrom^*, Mark E. Koina, M.W. Anders and Philip G. Board^*

From the John Curtin School of Medical Research,^* Australian National University, Canberra, Australia; the Department of Anatomical Pathology, The Canberra Hospital, Canberra, Australia; and the Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York

Abstract

Glutathione transferase zeta (GSTZ1-1) is the major enzyme that catalyzes the metabolism of -halo acids such as dichloroacetic acid, a carcinogenic contaminant of chlorinated water. GSTZ1-1 is identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the catabolic pathways for phenylalanine and tyrosine. In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype. Gstz1^–/– mice do not have demonstrable activity with maleylacetone and -halo acid substrates, and other GSTs do not compensate for the loss of this enzyme. When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney. The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice. GSTZ1-1-deficient mice showed constitutive induction of alpha, mu, and pi class GSTs as well as NAD(P)H:quinone oxidoreductase 1. The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate.

This article has been cited by other articles:

				K. Fujimoto, S. Arakawa, T. Watanabe, H. Yasumo, Y. Ando, W. Takasaki, S. Manabe, T. Yamoto, and S.-i. Oda Generation and Functional Characterization of Mice with a Disrupted Glutathione S-Transferase, Theta 1 Gene Drug Metab. Dispos., December 1, 2007; 35(12): 2196 - 2202. [Abstract] [Full Text] [PDF]

				K. I. Matthaei Genetically manipulated mice: a powerful tool with unsuspected caveats J. Physiol., July 15, 2007; 582(2): 481 - 488. [Abstract] [Full Text] [PDF]

				M. Jia, B. Coats, M. Chadha, B. Frentzen, J. Perez-Rodriguez, P. A. Chadik, R. A. Yost, G. N. Henderson, and P. W. Stacpoole Human Kinetics of Orally and Intravenously Administered Low-Dose 1,2-13C-Dichloroacetate. J. Clin. Pharmacol., December 1, 2006; 46(12): 1449 - 1459. [Abstract] [Full Text] [PDF]

				K. Fujimoto, S. Arakawa, Y. Shibaya, H. Miida, Y. Ando, H. Yasumo, A. Hara, M. Uchiyama, H. Iwabuchi, W. Takasaki, et al. Characterization of Phenotypes in Gstm1-null Mice by Cytosolic and in Vivo Metabolic Studies Using 1,2-Dichloro-4-Nitrobenzene Drug Metab. Dispos., September 1, 2006; 34(9): 1495 - 1501. [Abstract] [Full Text] [PDF]

				A. C. Blackburn, K. I. Matthaei, C. Lim, M. C. Taylor, J. Y. Cappello, J. D. Hayes, M. W. Anders, and P. G. Board Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways Mol. Pharmacol., February 1, 2006; 69(2): 650 - 657. [Abstract] [Full Text] [PDF]