Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity.
Boekelheide K; Anthony DC; Giangaspero F; Gottfried MR; Graham DG
Chem Res Toxicol 1988 Jul; 1(4):200-203
A study was made of the chemical reactivity and in-vivo effects of the delta diketone, 2,6-heptanedione (13505345) and the epsilon diketone, 2,7-octanedione (1626091). The relative amine reactivities of 2,5-hexanedione (110134), a gamma diketone, 2,6- heptanedione, and 2,7-octanedione were determined by incubation with ovalbumin. 2,6-Heptanedione derivatized ovalbumin lysyl epsilon amines more rapidly than 2,5-hexanedione. However, 2,7-octanedione did not decrease the free amine concentration of ovalbumin during incubation, being essentially incapable of forming long lived adducts with amines under biologic conditions since this would require the development of a seven membered ring. The diketones were incubated with ovalbumin and tritium labeled lysine to compare their relative cross linking abilities. To assess in-vivo toxicity, rats were given daily intraperitoneal injections of 4 millimoles of 2,6-heptanedione/kilogram. Only three of seven survived and after 11 weeks they exhibited generalized wasting but no detectable neuropathy. Nor was there any significant difference in the weight of the testes of treated rats. In a second study 2,6-heptanedione was administered in the drinking water as a 1 percent solution for 7 weeks, followed by a 10 week period of 2 percent 2,6-heptanedione exposure for an average daily dose of 11.3 millimoles/kilogram. No mortality occurred and no clinical neurotoxicity was noted. Testes weight was normal. Intraperitoneal injection of 2,7-octadione produced severe local inflammation. In the one surviving rat no clinical signs of neurotoxicity were noted and testes weight was normal. The neurotoxic potency of the gamma diketones was clearly dependent on their rate of pyrrole formation, identifying cyclization as an essential step in the development of an injury.
NIOSH-Publication; NIOSH-Grant; Laboratory-animals; Nervous-system-disorders; Testes; Reproductive-system-disorders; Metabolic-study; Carcinogenicity; Toxic-effects
Pathology and Lab Medicine Div. of Biology and Medicine Brown University, Box G Providence, RI 02912
13505-34-5; 1626-09-1; 110-13-4
Chemical Research in Toxicology
Brown University, Providence, Rhode Island