Biotransformation of nitrosobenzene, phenylhydroxylamine, and aniline in the isolated perfused rat liver

Eyer, Peter; Kampffmeyer, Hermann; Maister, H. G.; Rösch-Oehme, E.

doi:10.3109/00498258009033785

Cited by 40 publications

(11 citation statements)

References 49 publications

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“…1D there is a stoichiometry between drug concentration and cell density. It was calculated from drug kinetics (14,16) and metabolism (17) and on the basis of the known nuclear matrix localization of ADPRT (18,19) and the number of ADPRT molecules per cell (15) that nitroso drug at =400 molecules per molecule of ADPRT produces tumoricidal action. Direct chemical extraction of the drugs by chloroform/methanol (1:1) and NMR analysis in isolated systems (unpublished results) showed no covalent binding of nitroso drugs with nucleic acids; thus the drugs acted with a high degree of specificity on ADPRT.…”

Section: Inhibitory Effects On Tumor Proliferation and Tumoricidalmentioning

confidence: 99%

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

Rice

Hillyer

Harten

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACT6-Nitroso-1,2-benzopyrone and 3-nitrosobenzamide, two C-nitroso compounds that inactivate the eukaryotic nuclear protein poly(ADP-ribose) polymerase [NAD+:poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] at one zinc-ringer site, completely suppressed the proliferation of leukemic and other malignant human cells and subsequently produced cell death. Tumoricidal concentrations of the drugs were relatively harmless to normal bone marrow progenitor cells and to superoxide formation by neutrophil granulocytes. The cellular mechanism elicited by the C-nitroso compounds consists of apoptosis due to DNA degradation by the nuclear calcium/magnesiumdependent endonuclease. This endonuclease is maintained in a latent form by poly(ADP-ribosyl)ation, but inactivation of ADPRT by C-nitroso drugs derepresses the DNA-degrading activity. ADPRT is thus identified as a critical regulatory enzyme component of a DNA-binding multiprotein system that plays a central function in defining DNA structures in the intact cell.In pursuing the biological consequences of the inhibition of poly(ADP-ribose) polymerase [NAD+ :poly(adenosine diphosphate D-ribose) ADP-D-ribosyltransferase, ADPRT, EC 2.4.2.30] within intact cells we have developed a group of C-nitroso-substituted molecules that are the oxidation products of previously described ligands containing amino groups (1). These C-nitroso ligands uniquely oxidize one of the zinc fingers of ADPRT, resulting in zinc ion ejection and concomitant inactivation of the poly(ADP-ribosyl)ation activity of ADPRT without abrogating its binding to DNA (1). In the present paper we demonstrate a cytostatic and apoptotic action of two of these ADPRT ligands, 6-nitroso-1,2-benzopyrone (NOBP) and 3-nitrosobenzamide (NOBA), ¶ toward malignant human cells. The apoptotic effect was traced to the derepression of a calcium/magnesiumdependent endonuclease that under resting conditions is known to be inhibited by poly(ADP-ribosyl)ation (2). (85 Ci/mmol; 1 Ci = 37 GBq) was added per well and its incorporation into DNA following an 18-hr incubation was determined radiochemically (6). Proliferation was also monitored by direct cell counting. Since both assays were in agreement, the more convenient radiochemical test was used routinely. The tetrazolium reduction assay for cell viability (7), which was originally developed as a test for mitochondrial succinate dehydrogenase (8), was compared with trypan blue uptake and plating efficiency, and on the basis of positive correlation among the three assays, the more quantitative dye reduction method was adopted. MATERIALS AND METHODSClonigenic Studies. Human 855-2 and HL-60 leukemic cells were plated at 105 per ml and human and rhesus bone marrow mononuclear cells and human peripheral stem cells at 4 x 105 per ml, and assays for colony-forming units were performed as reported (5). A semiquantitative assessment of malignant cells in bone marrow specimens was done by flow cytometry with labeled fluorescein-conjugated antibodies against ...

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Section: Inhibitory Effects On Tumor Proliferation and Tumoricidalmentioning

confidence: 99%

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

Rice

Hillyer

Harten

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…4-Aminophenol (p-aminophenol, PAP) is a known metabolite of the analgesics paracetamol (acetaminophen) (Gemborys and Mudge 1981;Newton et al 1982) and phenacetin (4-phenetidine) (Smith and Griffiths 1976), the industrial chemical aniline (Kao et al 1978;Eyer et al 1980;Evelo et al 1984) and the pesticide isopropyl carbanilate (Paulson et al 1975). It is also used in photographic processing and along with other aminophenols as hair dyes (Anon 1988).…”

Section: Introductionmentioning

confidence: 99%

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

1993

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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. We have recently reported that a glutathione conjugate of PAP, 4-amino-3-S-glutathionylphenol, is more toxic to the kidney than the parent compound itself. In this study we have examined the distribution and covalent binding of radiolabel from 4-[ring 3H]-aminophenol in the plasma, kidney and liver of rats 24 h after dosing and related these findings to the extent of nephrotoxicity. In addition, we have examined the effect of ascorbic acid which will slow the oxidation of PAP; acivicin, an inhibitor of gamma-glutamyltransferase and hence the processing of glutathione-derived conjugates; and probenecid, an inhibitor of organic anion transport on the nephrotoxicity produced by PAP. Administration of a single dose of PAP at 458 or 687 mumol kg-1 produced a dose-related alteration in renal function within 24 h which was associated with proximal tubular necrosis. The lesion at the lower dose was restricted to the S3 proximal tubules in the medullary rays, while at the higher dose it additionally affected the S3 tubules in the pars recta region of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…However it has shown that nitrosobenzene is present in blood after aniline administration (32,33). Production of nitrosobenzene and/or phenylhydroxylamine from aniline has also been observed in microsomal systems (27) and in isolated perfused rat liver (34). The time course of methemoglobinemia in rats given aniline halogenated hydroxylamines is much different from that observed in rats treated with other phenylhydroxylamines.…”

Section: Electrophoretic Changesmentioning

confidence: 83%

Mechanistic study on aniline-induced erythrocyte toxicity

Singh

Purnell

2006

Toxicology Letters

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Strategies for the use of bio-indicators in the prediction of environmental damage should include mechanistic research. This study involves the relationship between the chemical structure and hemotoxic markers of aniline and its halogenated analogs. Aniline-induced methemoglobinemia, loss of circulating blood cells, blood stability, glutathione depletion and membrane cytoskeletal changes were assessed following exposure to phenylhydroxylamine (PHA), para-fluoro-, para-bromo-, and para-iodo in male Sprague-Dawley rats. Methemoglobin was determined spectrophotometrically at 635 nm. Erythrocyte depletion was investigated by loss of radioactivity in chromium-labeled red blood cells in vivo. Membrane proteins were analyzed by SDS-PAGE using red blood ghost cells treated with various aniline analogs. Results showed dose-and time-dependent changes in the induction of methemoglobin of up to 78 % with para-bromo PHA and 75 % with para-iodo PHA compared to 3 % to 5 % in control. Treated animals lost up to three times more blood from circulation compared to control within 14 days after treatment. Erythrocytes were more stable in buffer solution than in para-iodo-treated cells. Depletion of reduced glutathione in PHA and para-iodo-PHA treated red cells was also observed. Analysis of red cell skeletal membrane treated with para-iodo-PHA showed that protein band 2.1 became broader and band 2.2 diminished completely in some treatments. Dose-and time-dependent changes suggested the use of hemotoxic endpoints as potential biomarkers for assessing chemical and drug safety.

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Biotransformation of nitrosobenzene, phenylhydroxylamine, and aniline in the isolated perfused rat liver

Cited by 40 publications

References 49 publications

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

Induction of endonuclease-mediated apoptosis in tumor cells by C-nitroso-substituted ligands of poly(ADP-ribose) polymerase.

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

Mechanistic study on aniline-induced erythrocyte toxicity

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