Urinary Metabolites of Hydrazine in Male Fischer 344 Rats Following Inhalation or Intravenous Exposure

Background 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) is formed in the anesthesia circuit by the degradation of sevoflurane. Compound A is nephrotoxic in rats and undergoes metabolism by the mercapturic acid pathway in rats and humans to yield the mercapturates S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L -cysteine (compound 3) and S-[2(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cys teine (compound 5). These experiments were designed to examine the fate and nephrotoxicity of compound A-derived mercapturates in rats. Methods The deacetylation of compounds 3 and 5 by human and rat kidney cytosol and with purified acylases I and III was measured, and their nephrotoxicity was studied in male Fischer 344 rats. The metabolism of the deuterated analogs of compounds 3 and 5, [acetyl-2H3]S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl ]-N-acetyl-L-cysteine (compound 3-d3) and [acetyl-2H3]S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N -acetyl-L-cysteine (compound 5-d3), respectively, was measured. Results Compound 5, but not compound 3, was hydrolyzed by human and rat kidney cytosols and by acylases I and III. 19F nuclear magnetic resonance spectroscopic analysis showed no urinary metabolites of compound 3, but unchanged compound 5 and its metabolites 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazol e-4-carboxylic acid were detected in urine. Compound 5 (250 microM/kg) produced clinical chemical and morphologic evidence of renal injury in two of three animals studied. Conclusions Compounds 3 and 5 underwent little metabolism. Compound 5, but not compound 3, was mildly nephrotoxic. These results indicate that compound A-derived mercapturate formation constitutes a detoxication pathway for compound A.

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The isolation and identification of the urinary metabolites of isopropylcyclohexane from male Fischer-344 rats

Toxicology ◽

10.1016/0300-483x(87)90206-x ◽

1987 ◽

Vol 47 (1-2) ◽

pp. 234

Author(s):

Gerry M. Henningsen ◽

Isabel Lopez ◽

Jacqueline Roberts ◽

Kyung O. Yu ◽

M.Paul Serve

Keyword(s):

Urinary Metabolites ◽

Fischer 344 Rats ◽

Isolation And Identification ◽

Fischer 344

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Mutagenicity of HPLC-fractionated urinary metabolites from 2,4,6-trinitrotoluene-treated Fischer 344 rats

Environmental and Molecular Mutagenesis ◽

10.1002/(sici)1098-2280(1997)30:3<298::aid-em8>3.0.co;2-h ◽

1997 ◽

Vol 30 (3) ◽

pp. 298-302 ◽

Cited By ~ 10

Author(s):

L. R. Brooks ◽

R. W. Jacobson ◽

S. H. Warren ◽

M. J. Kohan ◽

K. C. Donnelly ◽

...

Keyword(s):

Urinary Metabolites ◽

Fischer 344 Rats ◽

Fischer 344

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Toxic effects of inhaled DMMP on the kidneys of Fischer-344 rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128687 ◽

1987 ◽

Vol 45 ◽

pp. 880-881

Author(s):

D.R. Mattie ◽

C.J. Hixson

Keyword(s):

Left Kidney ◽

Inhalation Exposure ◽

Electron Microscopic Examination ◽

Exposure Period ◽

Male Rats ◽

Continuous Exposure ◽

Fischer 344 Rats ◽

Electron Microscopic ◽

Thin Sections ◽

Fischer 344

Dimethylmethylphosphonate (DMMP) is a simple organophosphate used industrially as a flame retardant and to lower viscosity in polyester and epoxy resins. The military considered the use of DMMP as a nerve gas simulant. Since military use of DMMP involved exposure by inhalation, there was a need for a subchronic inhalation exposure to DMMP to fully investigate its toxic potential.Male Fischer-344 rats were exposed to 25 ppm or 250 ppm DMMP vapor on a continuous basis for 90 days. An equal number of control rats were sham-exposed. Following the 90-day continuous exposure period, 15 male rats were sacrificed from each group. Two rats from each group had the left kidney perfused for electron microscopic examination. The kidneys were perfused from a height of 150 cm water with 1% glutaraldehyde in Sorensen's 0.1M phosphate buffer pH 7.2. An additional kidney was taken from a rat in each group and fixed by immersion in 2.5% glutaraldehyde and 2% paraformaldehyde in 0.1M cacodylate buffer pH 7.4. A portion of the 9 kidneys collected for electron microscopy were processed into Epon 812. Thin sections, stained with uranyl acetate and lead citrate, were examined with a JEOL 100B Transmission Electron Microscope. Microvilli height was measured on photographs of the cells of proximal tubules. This data, along with morphologic features of the cells, allows the proximal convoluted tubules (PCT) to be identified as being S1, S2, or S3 segment PCT.

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Ultrastructure of rat alveolar macrophages activated in situ by poly:IC

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128158 ◽

1987 ◽

Vol 45 ◽

pp. 768-769

Author(s):

A. M. Klinkner ◽

R. A. Weiss ◽

A. Kelley ◽

P. J. Bugelski

Keyword(s):

Venous Blood ◽

Intratracheal Instillation ◽

Buffy Coat ◽

Fischer 344 Rats ◽

Blood Monocytes ◽

Fischer 344 ◽

Polyinosinic:Polycytidylic Acid ◽

Macrophage Activator ◽

Endogenous Peroxidase

Polyinosinic:polycytidylic acid is an inducer of interferon and a macrophage activator. We have found that intratracheal instillation of polyI:C (IT-pI:C) activates rat bronchoalveolar lavage cells (BAL) for a variety of functions. Examination of Giemsa stained, cytocentrifuge preparations showed that IT-pI:C induced a population of BAL not seen in resident BAL. The morphology of these cells suggested that they might be derived from blood monocytes. To test this hypothesis we have examined several populations of macrophages that had been stained for endogenous peroxidase activity as a marker of cells derived from the monocyte-macrophage lineage.Macrophages were obtained from Fischer 344 rats. Peritoneal exudate cells (PEC) were collected by lavage 4 days after i.p. injection of 20 ml 3% thioglycolate. Buffy coat monocytes were separated from venous blood from naive rats.

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