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Comparative neurotoxicity and pyrrole-forming potential of 2,5-hexanedione and perdeuterio-2,5-hexanedione in the rat.

Authors
DeCaprio-AP; Briggs-RG; Jackowski-SJ; Kim-JC
Source
Toxicol Appl Pharmacol 1988 Jan; 92(1):75-85
NIOSHTIC No.
00177890
Abstract
An investigation was conducted to compare the in-vitro and in-vivo pyrrole forming potential of 2,5-hexanedione (110134) (2,5-HD) and perdeuterio-2,5-hexanedione (P-2,5-HD) and to examine the neurotoxic potency of each isomer in rats. Male Sprague-Dawley-rats were injected intraperitoneally with 2,5-HD or P-2,5-HD each day, 5 days per week, at a dose of 3.5 millimoles per kilogram (mmol/kg) per day for 17 days, or 0.5mmol/kg per day for 38 days. In a separate study of tissue distribution after uptake of the two diketones, rats were given single intraperitoneal doses of 7.5mmol/kg of 2,5-HD or P-2,5- HD and then terminated 1, 2, 6 or 18 hours after dosing. Pyrrolylation of bovine serum albumin (BSA) in-vitro proceeded in a linear fashion for both isomers for incubation times of between 0.5 and 5 hours. Rats given 2,5-HD at either dose progressed to moderate or marked levels of clinical neuropathy at the time of termination. Numerous swollen axons were seen in sections of thoracic and lumbar spinal cord from 2,5-HD treated rats. Testicular alterations were seen in the 2,5-HD, but not P-2,5-HD, treated rats. In general, pyrrole adduct concentrations were two to three times higher in serum and in axonal cytoskeletal proteins from the 2,5-HD treated rats than in proteins from the P-2,5-HD treated rats. Levels of covalently crosslinked, high molecular weight protein were generally significantly lower in preparations from P- 2,5-HD treated rats. Tissue distribution analysis showed no significant differences between tissue concentrations of the two isomers. In experiments on deuterium/hydrogen exchange rates in- vivo, essentially all the exchange detected in the whole P-2,5-HD molecule was attributable to loss of deuterium from the terminal methyl groups. The authors conclude that pyrrole formation is required for diketone neurotoxicity.
Keywords
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Laboratory-animals; Ketones; Neurotoxicity; Comparative-toxicology; Isotope-effect; Histopathology; Neuropathology; Pathomorphology; Toxicopathology
Contact
Biochem and Genetic Toxicology New York State Dept of Health Empire State Plaza Albany, N Y 12201
CODEN
TXAPA9
CAS No.
110-13-4
Publication Date
19880101
Document Type
Journal Article
Funding Amount
133853
Funding Type
Grant
Fiscal Year
1988
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-01972
Issue of Publication
1
ISSN
0041-008X
Priority Area
Neurotoxic Disorders; Neurotoxic-effects
Source Name
Toxicology and Applied Pharmacology
State
NY
Performing Organization
New York State Dept of Health, New York, New York
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