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.

Comparison of location, severity, and dose response of proximal axonal lesions induced by 3,3'-iminodipropionitrile and deuterium substituted analogs.

Administration of 3,3'-iminodipropionitrile (IDPN) to rats results in massive accumulation of tangled neurofilaments in the proximal axons of large neurons, such as in dorsal root ganglia (DRG) and ventral horns of the lumbar spinal cord (LSC). Clinically, rats develop hyperexcitability, circling, head bobbing, and retropulsion. The ultimate toxicant and the molecular mechanism are not known. In a study designed to explore potential activation and detoxification pathways, dose-related differences in location and severity of lesions were observed in rats treated with IDPN or deuterium substituted analogs, 2,2,2',2'-tetradeuterio-IDPN (2-d-IDPN) or 3,3,3',3'-tetradeuterio-IDPN (3-d-IDPN). The compounds or saline were administered intraperitoneally to three rats per group at dose levels of 3.0, 1.5, 1.0, and 0.0 mmole/kg/day for 3 days. One week after the initial dose, tissues from DRG and LSC were collected, prepared and evaluated histologically in zones extending from areas adjacent to the cell bodies, distally toward the DRG stalk or toward the lumbar spinal roots. In the low dose IDPN group, DRG and LSC lesions were most prominent in distal zones. As dosage increased, the lesions progressed in severity and in proximity to the cell bodies. At the high dose, lesions were prominent in all zones. The same general pattern occurred with both analogs, although 2-d-IDPN was less potent than IDPN and 3-d-IDPN was more potent than IDPN. The differences in potency from the secondary isotopic effect of deuterium suggest that the 3-position is important in detoxification while the 2-position is important in the bioactivation of IDPN.

The propionic acids. Gastrointestinal toxicity in various species.

The propionic acids represent the largest chemical class of nonsteroidal anti-inflammatory agents (NSAID). Several of them are widely used, both in the United States and internationally. This paper discusses observations made on fenoprofen, flurbiprofen, ibuprofen and naproxen. Of these compounds, three are racemates; the fourth, naproxen, is an enantiomer. As a group, the propionic acids, along with most members of the other classes of NSAID, produce gastrointestinal damage in most species. These lesions vary from erythema, hemorrhage and erosion to ulceration and peritonitis. As might be expected, the degree of gastrointestinal intolerance depends on many factors: the individual compound, the dose-level, the duration of the period of drug administration, and the pharmacokinetics and metabolism in a given species. For example, in our experience the rat is less tolerant of NSAID than is the monkey, and the dog is less tolerant than the rat. Gastrointestinal lesions have been seen following both parenteral and oral administration; these findings suggest that factors other than local irritation play a role in the development of lesions. Most NSAID inhibit prostaglandin cyclo-oxygenase activity, which results in a prostaglandin deficiency at the tissue level. The administration of relevant exogenous prostaglandins, such as 16,16-dimethyl PGE2, has been shown to inhibit the gastrointestinal toxicity accompanying the administration of several NSAID, including some of the propionic acids.

Host factors affecting perinatal carcinogenesis by resorptive alkylnitrosoureas in rats.

Host factors are operative in transplacental carcinogenesis. There are species, strain, sex, and individual differences in susceptibility to carcinogens. Rat fetuses are over 50 times more susceptible than adults to the oncogenic effects of ENU, yet are less susceptible to tumor induction with DMN. Immune mechanisms do not seem to affect the latency period, incidence, location, and type of neurogenic neoplasms, although tumor-specific antigens are demonstrable in neoplastic neuroectodermal cells. Although placental barriers, DNA repair capacities, age at exposure, hormonal interaction, and immune responsiveness may be singled out as possible causes for species, strain, sex, and individual variations in susceptibility to the neuro-oncogenic potential of ENU, no definitive proof of the mechanism of action of any of these factors has yet been presented.

Tumor-specific transplantation immunity to intracerebral challenge with cells from a methylnitrosourea- induced brain tumor.

Tumor-specific transplantation immunity was demonstrated in syngenic rats immunized and challenged with tumor cells (T9) from an N-methyl N-nitrosourea-induced brain tumor. All unimmunized rats and rats pretreated with normal glial cells in complete Freund's adjuvant or with adjuvant alone died of intracerebral (i.c.) neoplasia at approximately 3 weeks post-challenge. Rats which were immunized with T9 cells with or without adjuvant failed to develop i.c. tumors by 6 weeks even though the challenge dose was 2 logs greater than a dose which consistently resulted in neoplasia in unimmunized rats.