[125I]endothelin binding in rat cerebellum is increased following L-2-chloropropionic-acid-induced granule cell necrosis.

The systemic administration of L-2-chloropropionic acid (L-CPA) to rats produced a marked depletion of cerebellar granule cells (> 80% of the total) when administered in a single oral dose of 750 or 250 mg/kg/day for 3 days. The nature of the L-CPA-induced neurotoxicity is currently unknown but it exhibits a number of features in common with excitatory amino acid-induced neuronal cell death. We observed an increase in [125I]endothelin-1 (ET-1) binding in the cerebellar cortex, as measured by quantitative receptor autoradiography, which occurs at 48 h, but not 24 h, following the 750 mg/kg L-CPA dosing regimen.

Strychnine and glycine protect renal proximal tubules from various nephrotoxicants and act in the late phase of necrotic cell injury.

We have previously shown that strychnine mimics the cytoprotective properties of glycine in renal proximal tubule (RPT) suspensions exposed to antimycin A (AA). The aims of this study were to determine whether the cytoprotective properties of strychnine applied to various types of nephrotoxicants and to examine the temporal aspects of the cytoprotection of glycine and strychnine. Tubular release of LDH activity was used as a marker of cell death.

Nephrotoxicity of 4-amino-3-S-glutathionylphenol and its modulation by metabolism or transport inhibitors.

The nephrotoxicity of 4-amino-3-S-glutathionylphenol (PAP-GSH), a known metabolite of 4-amino-phenol (PAP), was determined in male Fischer 344 rats. Administration of a single dose of 40 or 60 mumol kg-1 caused a marked elevation in blood urea nitrogen and an increase in the urinary excretion of glucose, protein and gamma-glutamyltransferase (GGT). These changes were associated with histological alterations in the proximal tubule, where at the lower dose the lesion was restricted to the S3 region of the proximal tubule in the medullary rays, while at the higher dose the lesion extended to affect the S3 region in both the medullary rays and the outer stripe of the outer medulla.

Immunohistochemical localisation of six glutathione S-transferases within the nasal cavity of the rat.

Many xenobiotics induce lesions within the nasal cavity of experimental animals which are site specific. This site selectivity may be due to regional deposition within the nasal cavity and/or the localisation of biotransformation enzymes. We have developed methodology which allows immunohistochemical localisation of xenobiotic biotransformation enzymes in transverse sections of the rat nasal cavity identical to those normally taken for pathological examination.

Cytosolic C-S lyase activity in human kidney samples-relevance for the nephrotoxicity of halogenated alkenes in man.

Human renal cortex cytosolic samples were screened for C-S lyase (EC 4.4.1.

Effects of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone on hepatic haem biosynthesis: species differences in hepatic porphyria.

2-[1-(Ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone (ETC) is a novel alkyl ketone herbicide. Continuous administration of ETC to mice for 28 days resulted in marked liver enlargement and severe intrahepatic cholestasis. These effects have been shown to result directly from a rapid and marked accumulation of porphyrin in the liver.

Studies on the mechanism of 4-aminophenol-induced toxicity to renal proximal tubules.

4-Aminophenol (PAP) is known to cause nephrotoxicity in the rat where it produces selective necrosis to renal proximal tubules. The aim of this work was to investigate the toxicity of PAP and its known nephrotoxic metabolite 4-amino-3-S-glutathionylphenol using a well defined suspension of rabbit renal proximal tubules. PAP at a concentration of 0.

An in vitro model of renal proximal tubule cell regeneration.

The ability of renal cells to regenerate is critical for the recovery of renal function following injury. Research on the recovery of renal function has been limited by the lack of in vitro models of renal repair. The goal of this study was to develop an in vitro model of renal proximal tubule cell (RPTC) injury and regeneration using primary cultures of rabbit RPTC.

Studies on the renal transport of trimethylpentanoic acid metabolites of 2,2,4-trimethylpentane in rat renal cortical slices.

2,2,4-Trimethylpentane (TMP), a nephrotoxic component of unleaded gasoline in male but not female rats, undergoes oxidative metabolism to yield 2,2,4- and 2,4,4-trimethylpentanol, pentanoic acid and 5-hydroxypentanoic acid. We have examined the effect of three of these pentanoic acid metabolites on the renal transport of the organic anion p-aminohippurate (PAH) and the organic cation tetraethylammonium (TEA) in renal cortical slices from male Fischer 344 rats. 2,4,4-Trimethylpentanoic acid, the major urinary metabolite in rats, produced a selective decrease in the accumulation of PAH without affecting TEA accumulation.

Isolation and expression of a cDNA coding for rat kidney cytosolic cysteine conjugate beta-lyase.

The role of rat kidney cysteine conjugate beta-lyase in the production of nephrotoxic thiols from S-cysteine conjugates of xenobiotics has been well established. However, the factors controlling the cellular distribution and substrate specificity of the enzyme have yet to be elucidated. As an approach to this we have isolated a cDNA for cysteine conjugate beta-lyase from a rat kidney cDNA library, using a combination of immunological and hybridization screening.

Differential cellular effects in the toxicity of haloalkene and haloalkane cysteine conjugates to rabbit renal proximal tubules.

The relationship between the covalent binding, uptake, and toxicity produced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC) was investigated in suspensions of rabbit renal proximal tubules (RPT). The DCVC and TFEC at concentrations of 25 microM produced a time-dependent (1-6 hours) loss of RPT viability. The TFEC was biotransformed rapidly by beta-lyase to a reactive metabolite which bound covalently to tubular protein.

The characterization of glutathione S-transferases from rat olfactory epithelium.

The glutathione S-transferases (GSTs) of rat olfactory epithelium have been characterized with regard to substrate specificity and subunit composition and compared to those of the liver. The presence of cytosolic GST activity in rat olfactory epithelium was confirmed and, using 1-chloro-2,4-dinitrobenzene as substrate, was found to be approximately one-third that of the liver. Olfactory microsomal GST activity was greater than that of liver microsomes and could be activated by treatment with the sulphydryl agent N-ethylmaleimide.

Dose-dependent induction or depression of cysteine conjugate beta-lyase in rat kidney by N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine.

The influence of N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine (NAc-PCBD) on cysteine conjugate beta-lyase in female rat kidney has been examined. After a single, non-nephrotoxic dose of NAc-PCBD (3 mg/kg), cytosolic beta-lyase enzyme activity was increased 1.5 to 3-fold commensurate with a corresponding increase in enzyme protein levels as assessed by both Western blot and ELISA analyses.

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria. Studies with a novel porphyrogenic agent.

1-[4-(3-Acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-eth yl propionaldehyde oxime (for short ATMP) is a novel porphyrogenic agent causing hepatic protoporphyria in the mouse. Mice given a single dose of the drug showed 24 h later a 70% inhibition of liver ferrochelatase and marked accumulation of protoporphyrin. These changes were not seen in similarly treated rats, guinea pigs, hamsters or chick embryos.

Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat.

4-Aminophenol (p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to cellular macromolecules.

Toxicology of sensory systems: a perspective.

This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed.

Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase.

Liver transplantation is the only effective treatment for hereditary tyrosinaemia type I (McKusick 276700). We have treated one acute and four subacute-chronic cases with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.

The accumulation and metabolism of 3-trifluoromethylpyridine by rat olfactory and hepatic tissues.

The accumulation of [methyl-14C]3-trifluoromethylpyridine (14C-3-FMP) by rat olfactory and hepatic tissue in vivo and in vitro has been investigated. 14C-3-FMP accumulates rapidly and selectively in both tissues in vivo, with an appreciable proportion of this activity being associated with the protein macromolecular fractions. Similar results were seen when isolated tissues were incubated in vitro in the presence of 14C-3-FMP.

Inhibition of ferrochelatase and accumulation of porphyrins in mouse hepatocyte cultures exposed to porphyrinogenic chemicals.

The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25 microM), EDDC (25 microM) and griseofulvin (25 microM) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium.

Nephrotoxicity of 4-aminophenol glutathione conjugate.

4-Aminophenol (p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known, but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to tissue macromolecules.

Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates.

The role of lipid peroxidation in the cell death produced by the haloalkene cysteine conjugates S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBC), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was investigated using a well-defined suspension of rabbit renal proximal tubules. PCBC, DCVC, TFEC, and CTFC at a concentration of 25 microM caused renal proximal tubular death (measured by lactate dehydrogenase release) in a time-dependent (2-6 hr) manner and increased tubular malondialdehyde (MDA) formation prior to and during cell death (1-6 hr). The antioxidants butylated hydroxytoluene (BHT) (25 microM) and N,N'-diphenyl-1,4-phenylenediamine (DPPD) (50 microM) and the iron chelator deferoxamine (1 mM) blocked the increase in MDA formation produced by these four compounds.

Pentachlorobutadienyl-L-cysteine (PCBC) toxicity: the importance of mitochondrial dysfunction.

The relationship between the covalent binding, uptake, and toxicity produced by pentachlorobutadienyl-L-cysteine (PCBC) was examined in rabbit renal proximal tubules (RPT), renal basolateral membrane vesicles, and isolated renal cortical mitochondria. Renal proximal tubules rapidly metabolized PCBC to a reactive intermediate that bound to tubular protein. Approximately 70-90% of PCBC found in the cell at any given time was bound to protein.