Immunohistochemical localization of glutamine transaminase K, a rat kidney cysteine conjugate beta-lyase, and the relationship to the segment specificity of cysteine conjugate nephrotoxicity.

Rat kidney glutamine transaminase K is a major rat kidney cysteine conjugate beta-lyase and is a key enzyme in the nephrotoxicity of some cysteine conjugates. However, it has not been demonstrated that the beta-lyase is present in the target cells. Furthermore, although all segments of the proximal tubule are affected by high doses of nephrotoxic cysteine conjugates, the S3 segment is the most sensitive. Because heterogeneous distribution of the beta-lyase could account for the enhanced sensitivity, antibody raised against rat kidney cysteine conjugate beta-lyase has been prepared and used to investigate the distribution of the enzyme in kidney and other tissues. The data show that the enzyme is highest in rat kidney, consistent with enzyme activity data. By immunohistochemical staining, no enzyme is present in the glomeruli or distal tubular elements of the kidney. The enzyme is present only in the target cells, the renal proximal tubular epithelium. However, the distribution of the beta-lyase within the proximal tubule is not consistent with the hypothesis that a higher concentration of the enzyme in the S3 segment accounts for the greater sensitivity of S3 to nephrotoxic cysteine conjugates compared to S1 and S2. Several alternative hypotheses are discussed.

• Publication year

  1988

• Venue

  Molecular Pharmacology

• Publication date

  1988-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/s0026-895x(25)09884-0PMID 3193955
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cellular effects of reactive intermediates: Nephrotoxicity of S-conjugates of amino acids

  2004cited by this paper
• The role of mitochondrial matrix enzymes in the metabolism and toxicity of cysteine conjugates.

  1988cited by this paper
• Renal transport processes and glutathione conjugate-mediated nephrotoxicity.

  1987cited by this paper
• Cysteine S-conjugates.

  1987cited by this paper
• The transport of S-cysteine conjugates in LLC-PK1 cells and its role in toxicity.

  1987cited by this paper
• Enzymatic transformation of mercapturic acids derived from halogenated alkenes to reactive and mutagenic intermediates.

  1987cited by this paper
• Toxicity of S-pentachlorobutadienyl-L-cysteine studied with isolated rat renal cortical mitochondria.

  1987cited by this paper
• Mechanism of S-(1,2-dichlorovinyl)-L-cysteine- and S-(1,2-dichlorovinyl)-L-homocysteine-induced renal mitochondrial toxicity.

  1987cited by this paper
• Biologically active intermediates generated by the reduced glutathione conjugation pathway. Toxicological implications.

  1986cited by this paper
• A purified cysteine conjugate beta-lyase from rat kidney cytosol. Requirement for an alpha-keto acid or an amino acid oxidase for activity and identity with soluble glutamine transaminase K.

  1986cited by this paper
• The role of glutathione conjugate metabolism and cysteine conjugate beta-lyase in the mechanism of S-cysteine conjugate toxicity in LLC-PK1 cells.

  1986cited by this paper
• The mechanism of pentachlorobutadienyl-glutathione nephrotoxicity studied with isolated rat renal epithelial cells.

  1986cited by this paper
• Cysteine conjugate beta-lyase activities in rat kidney cortex: subcellular localization and relationship to the hepatic enzyme.

  1985cited by this paper
• Isolation and characterization of a rat liver enzyme with both cysteine conjugate beta-lyase and kynureninase activity.

  1985cited by this paper
• Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates.

  1985cited by this paper
• Nephrotoxicity of S-(2-chloro-1,1,2-trifluoroethyl)glutathione and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, the glutathione and cysteine conjugates of chlorotrifluoroethene.

  1985cited by this paper
• Chronic toxicity of S‐(trans‐1,2‐dichlorovinyl)‐L‐cysteine in mice

  1984cited by this paper
• The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity.

  1984cited by this paper
• Purification and characterization of a rat liver enzyme catalyzing N-deacetylation of mercapturic acid conjugates.

  1981cited by this paper
• Effects of inhaled chlorotrifluoroethylene and hexafluoropropene on the rat kidney.

  1981cited by this paper
• Renal transtubular transport of mercapturic acid in vivo.

  1981cited by this paper
• Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.

  1981cited by this paper
• Purification of soluble and mitochondrial glutamine transaminase K from rat kidney. Use of a sensitive assay involving transamination between L-phenylalanine and alpha-keto-gamma-methiolbutyrate.

  1978cited by this paper
• Ischemic damage and repair in the rat proximal tubule: differences among the S1, S2, and S3 segments.

  1978cited by this paper
• Properties of DNA treated with S-(1,2-dichlorovinyl)-L-cysteine and a lyase.

  1972cited by this paper
• A study by micropuncture and microdissection of acute renal damage in rats.

  1968cited by this paper

• The Metabolic Importance of the Glutaminase II Pathway in Normal and Cancerous Cells.

  2020cites this paper
• Tetrachloroethylene [MAK Value Documentation, 2017]

  2019cites this paper
• Clinical Practice: Mini-Review

  2019cites this paper
• High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in ‘Glutamine Addiction’

  2019cites this paper
• Metabolism of Glutathione S-Conjugates: Multiple Pathways

  2017cites this paper
• Tetrachlorethen [MAK Value Documentation in German language, 2017]

  2017cites this paper
• Hexachlorbutadien [MAK Value Documentation in German language, 2016]

  2016cites this paper
• Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

  2014cites this paper
• α-Ketoglutaramate: an overlooked metabolite of glutamine and a biomarker for hepatic encephalopathy and inborn errors of the urea cycle

  2014cites this paper
• Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal.

  2012cites this paper
• Renal Xenobiotic Metabolism

  2010cites this paper
• Enzymes Involved in Processing Glutathione Conjugates

  2010cites this paper
• Measurement of cysteine S-conjugate β-lyase activity.

  2010cites this paper
• Differential Localization of Flavin-Containing Monooxygenase (FMO) Isoforms 1, 3, and 4 in Rat Liver and Kidney and Evidence for Expression of FMO4 in Mouse, Rat, and Human Liver and Kidney Microsomes

  2009cites this paper
• Studies on the comparative toxicity of S-(1,2-dichlorovinyl)-L-cysteine, S-(1,2-dichlorovinyl)-L-homocysteine and 1,1,2-trichloro-3,3,3-trifluoro-1-propene in the Fischer 344 rat

  2009cites this paper
• Cysteine conjugate beta-lyase activity of rat erythrocytes and formation of beta-lyase-derived globin monoadducts and cross-links after in vitro exposure of erythrocytes to S-(1,2-dichlorovinyl)-L-cysteine.

  2009cites this paper
• Role of Cysteine S-Conjugate β-Lyases in the Bioactivation of Renal Toxicants

  2008cites this paper
• Methods for Measuring Cysteine S‐Conjugate β‐Lyase Activity

  2007cites this paper
• Formation of three N-acetyl-L-cysteine monoadducts and one diadduct by the reaction of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide with N-acetyl-L-cysteine at physiological conditions: chemical mechanisms and toxicological implications.

  2007cites this paper
• Acute, nonfatal intoxication with trichloroethylene

  2007cites this paper
• Cysteine S-conjugate beta-lyases.

  2006cites this paper
• Effects of Uninephrectomy and Mercuric Chloride on Renal Glutathione Homeostasis 1

  2006cites this paper
• Cysteine S-conjugate b-lyases Review Article

  2006cites this paper
• Cysteine S-conjugate β-lyases

  2006cites this paper
• Cisplatin-induced toxicity is associated with platinum deposition in mouse kidney mitochondria in vivo and with selective inactivation of the alpha-ketoglutarate dehydrogenase complex in LLC-PK1 cells.

  2006cites this paper
• Mechanisms of cysteine S-conjugate beta-lyases.

  2006cites this paper
• Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice

  2005cites this paper
• Dichlorovinyl cysteine (DCVC) in the mouse kidney: tissue-binding and toxicity after glutathione depletion and probenecid treatment

  2004cites this paper
• Structural characterization, tissue distribution, and functional expression of murine aminoacylase III.

  2004cites this paper
• The role of glutamine transaminase K (GTK) in sulfur and alpha-keto acid metabolism in the brain, and in the possible bioactivation of neurotoxicants.

  2004cites this paper
• Enzyme-Catalyzed Activation of Anticancer Prodrugs

  2004cites this paper
• Role of cysteine S-conjugate beta-lyase in the metabolism of cisplatin.

  2003cites this paper
• Role of Cysteine S-Conjugate β-Lyase in the Metabolism of Cisplatin

  2003cites this paper
• Evidence for Trichloroethylene Bioactivation and Adduct Formation in the Rat Epididymis and Efferent Ducts1

  2003cites this paper
• Renal cysteine conjugate C-S lyase mediated toxicity of halogenated alkenes in primary cultures of human and rat proximal tubular cells

  2003influential citation
• Development of resistance against hexachlorobutadiene in the proximal tubules of young male rat.

  2003cites this paper
• Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism.

  2002cites this paper
• Hepatic and renal toxicities associated with perchloroethylene.

  2001influential citation
• Cysteine conjugate of methazolamide is metabolized by β‐lyase

  2001cites this paper
• (cid:2) -Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin

  2001cites this paper
• Cysteine conjugate of methazolamide is metabolized by beta-lyase.

  2001cites this paper
• Immunohistochemical localization of the acylases that catalyze the deacetylation of N-acetyl-L-cysteine and haloalkene-derived mercapturates.

  2000cites this paper
• Metabolism of trichloroethylene.

  2000cites this paper
• Modes of action of trichloroethylene for kidney tumorigenesis.

  2000cites this paper
• Organ-specific carcinogenicity of haloalkenes mediated by glutathione conjugation

  1999cites this paper
• Mercapturic acids as biomarkers of exposure to electrophilic chemicals:applications to environmental and industrial chemicals.

  1998cites this paper
• Renal drug metabolism.

  1998cites this paper
• Glutathione-dependent bioactivation of haloalkenes.

  1998cites this paper
• Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants

  1998cites this paper
• Mechanistic Analysis ofS-(1,2-Dichlorovinyl)-l-cysteine-Induced Cataractogenesisin Vitro

  1997cites this paper
• Mechanistic analysis of S-(1,2-dichlorovinyl)-L-cysteine-induced cataractogenesis in vitro.

  1997cites this paper
• Intranephron distribution of cysteine S -conjugate β-lyase activity and its implication for hexachloro-1,3-butadiene-induced nephrotoxicity in rats

  1997influential citation
• Localization of polymorphic N-acetyltransferase (NAT2) in tissues of inbred mice.

  1997cites this paper
• Inactivation of brain and kidney aspartate aminotransferases by S-(1,2,-dichlorovinyl)-L-cysteine and by S-(1,1,2,2,-tetrafluoroethyl)-L-cysteine.

  1996cites this paper
• Site specific drug and xenobiotic induced renal toxicity.

  1996cites this paper
• Cloning and expression of a rat kidney cytosolic glutamine transaminase K that has strong sequence homology to kynurenine pyruvate aminotransferase.

  1996cites this paper
• Bone marrow and renal injury associated with haloalkene cysteine conjugates in calves

  1996cites this paper
• Short Communication: Urinary excretion of glutamine transaminase K as an early index of mercuric chloride-induced nephrotoxicity.

  1996cites this paper
• Glutamine transaminase K is not a major cysteine S-conjugate beta-lyase of rat kidney mitochondria: evidence that a high-molecular weight enzyme fulfills this role.

  1995cites this paper
• Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics.

  1995cites this paper
• Metabolism and kinetics of trichloroethylene in relation to toxicity and carcinogenicity. Relevance of the mercapturic acid pathway.

  1995cites this paper
• Renal activation of trichloroethene and S-(1,2-dichlorovinyl)-L-cysteine and cell proliferative responses in the kidneys of F344 rats and B6C3F1 mice.

  1995cites this paper
• Isolation from Rat Kidney of a Cytosolic High Molecular Weight Cysteine-S-Conjugate -Lyase with Activity toward Leukotriene E(*)

  1995cites this paper
• Enzymology of Cysteine S-Conjugote β-Lyases

  1994cites this paper
• Formation and fate of nephrotoxic and cytotoxic glutathione S-conjugates: cysteine conjugate beta-lyase pathway.

  1994cites this paper
• Cytosolic C-s lYase Activity in Human Kidney Samples-Relevance for the Nephrotoxicity of Halogenated Alkenes in Man

  1994cites this paper
• Inhibition of S-(1,2-dichlorovinyl)-L-cysteine-induced lipid peroxidation by antioxidants in rabbit renal cortical slices: dissociation of lipid peroxidation and toxicity.

  1994cites this paper
• Roles of cysteine conjugate beta-lyase and S-oxidase in nephrotoxicity: studies with S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-L-cysteine sulfoxide.

  1994cites this paper
• Ammonia metabolism in mammals: interorgan relationships.

  1993cites this paper
• Isolation and expression of a cDNA coding for rat kidney cytosolic cysteine conjugate beta-lyase.

  1993cites this paper
• Frog Skin: A Computer Simulation of Experiments Performed on Frog Skin In Vitro to Investigate the Epithelial Transport of Ions

  1993cites this paper
• High activities of glutamine transaminase K (dichlorovinylcysteine beta-lyase) and omega-amidase in the choroid plexus of rat brain.

  1993cites this paper
• Bovine Pulmonary, Hepatic and Renal Tissues: Models for the Study of Mammalian C-S Lyase Enzymes

  1993cites this paper
• Purification of glutamine transaminase K/cysteine conjugate beta-lyase from rat renal cytosol based on hydrophobic interaction HPLC and gel permeation FPLC.

  1993cites this paper
• High Activities of Glutamine Transaminase K (Dichlorovinylcysteine β‐Lyase) and ω‐Amidase in the Choroid Plexus of Rat Brain

  1993cites this paper
• COR pulmonale is caused by monocrotaline and dehydromonocrotaline, but not by glutathione or cysteine conjugates of dihydropyrrolizine.

  1993cites this paper
• Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells.

  1992cites this paper
• Human hepatic CS lyase: Transamination reactions and significant differences between kynurenine aminotransferase and kynureninase

  1992cites this paper
• Bioactivation of xenobiotics by formation of toxic glutathione conjugates.

  1991cites this paper
• Detection of cysteine conjugate metabolite adduct formation with specific mitochondrial proteins using antibodies raised against halothane metabolite adducts.

  1991cites this paper
• Acute effects of the D-isomer of S-(1,2-dichlorovinyl)cysteine on renal function and ultrastructure in the pentobarbital-anesthetized dog: site-specific toxicity involving the S1 and S2 cells of the proximal tubule.

  1991cites this paper
• Reactivity of cysteine S-conjugate sulfoxides: formation of S-[1-chloro-2-(S-glutathionyl)vinyl]-L-cysteine sulfoxide by the reaction of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide with glutathione.

  1991cites this paper
• Is the toxicity of cysteine conjugates formed during mercapturic acid biosynthesis relevant to the toxicity of covalently bound drug residues?

  1990cites this paper
• Molecular and biochemical mechanisms of chemically induced nephrotoxicity: a review.

  1990cites this paper
• Glutamine Transaminase K and Cysteine Conjugate β‐Lyase a

  1990cites this paper
• Glutamine transaminase K and cysteine conjugate beta-lyase.

  1990cites this paper
• Bioactivation of hexachlorobutadiene by glutathione conjugation.

  1990cites this paper
• Effects of uninephrectomy and mercuric chloride on renal glutathione homeostasis.

  1990cites this paper
• Assessment of S-(1,2-dichlorovinyl)-L-cysteine induced toxic events in rabbit renal cortical slices. Biochemical and histological evaluation of uptake, covalent binding, and toxicity.

  1990cites this paper
• Glutathione conjugate mediated toxicities.

  1990cites this paper
• In vitro and in vivo nephrotoxicity of the L and D isomers of S-(1,2-dichlorovinyl)-cysteine.

  1989cites this paper
• N-acetyl S-(1,2-dichlorovinyl)-L-cysteine produces a similar toxicity to S-(1,2-dichlorovinyl)-L-cysteine in rabbit renal slices: differential transport and metabolism.

  1989cites this paper
• Transport and activation of S-(1,2-dichlorovinyl)-L-cysteine and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine in rat kidney proximal tubules.

  1989cites this paper