In vitro toxicological investigations of isoxazolinone amino acids of Lathyrus sativus.
Two non-protein amino acids of Lathyrus sativus, beta-(isoxazoline-5-on-2-yl)-alanine (BIA) and its higher homologue alpha-amino-gamma-(isoxazoline-5-on-2-yl)-alanine (ACI) were tested for excitotoxic potential. BIA (0.5-2.0 mM) but not ACI (2.0 mM) produced a concentration-dependent neurodegeneration in mouse cortical explants. The neuronal damage was prevented by the prior and simultaneous application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), indicating that it was mediated by non-N-methyl-D-aspartate type receptors. BIA (0.5-2.0 mM) activated CNQX-sensitive currents which were significantly smaller than those activated by 3-N-oxalyl-L-2,3-diaminopropanoic acid (beta-ODAP) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the majority of neurons. In a small number of cells, BIA (2 mM) produced currents which were similar in amplitude to those activated by beta-ODAP (50 microM). These results suggest that Lathyrus sativus plants engineered to block the synthesis of beta-ODAP may accumulate a neurotoxic precursor and therefore must be tested for the presence of both BIA and beta-ODAP.
Riepe
M
M
Center for Research on Environmental and Occupational Toxicology, Oregon Health Sciences University, Portland 97201-3098, USA.
Spencer
P S
PS
Lambein
F
F
Ludolph
A C
AC
Allen
C N
CN
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000409:Alanine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D000613:Aminobutyrates / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D004594:Electrophysiology; D006624:Hippocampus / Q000473:pathology; D007555:Isoxazoles / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity*; D007842:Lathyrism / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D009044:Motor Cortex / Q000473:pathology; D009410:Nerve Degeneration / Q000187:drug effects; D010947:Plants, Toxic / Q000737:chemistry*
D000613:Aminobutyrates; D007555:Isoxazoles; C074507:(isoxazolin-5-on-2-yl)alanine; C083644:2-(3-amino-3-carboxypropyl)isoxazolin-5-one; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000409:Alanine