Metabolism of 3,3'-iminodipropionitrile and deuterium-substituted analogs: potential mechanisms of detoxification and activation.

3,3'-Iminodipropionitrile (IDPN), a neurotoxicant that causes an excitatory CNS syndrome and a proximal axonopathy, is metabolized to beta-aminopropionitrile (BAPN), cyanoacetic acid (CAA), and beta-alanine (beta-ala) in rats. None of these metabolites are neurotoxic, suggesting that they are products of detoxification. To investigate potential pathways of activation and detoxification, we treated groups of rats with saline, IDPN, or deuterium-substituted analogs, 2,2,2',2'-tetradeuterio-IDPN (2-d-IDPN) or 3,3,3',3'-tetradeuterio-IDPN (3-d-IDPN) at 3 mmol/kg/day for 3 days. beta-Alanine was isolated from urine by ion-exchange chromatography and analyzed by GC-MS and HPLC. The position of the deuterium labels on beta-ala indicates that beta-ala is derived by hydrolysis of IDPN and that the carboxylate of beta-ala is derived from the nitrile of IDPN. Excretion of CAA, measured by GC-MS, is markedly reduced in 3-d-IDPN-treated rats. Since 3-d-IDPN is more potent than equimolar doses of IDPN, the diminished excretion of CAA may be due to an isotopic effect in retarding the hydrolysis of IDPN to BAPN and CAA. The finding that 2-d-IDPN is less potent than IDPN suggests that activation of IDPN may occur near the 2-position. Although nitrile hydrolysis is established, the mechanism is not yet clear.