Metabolism of 3,3′-Iminodipropionitrile and Deuterium-Substituted Analogs: Potential Mechanisms of Detoxification and Activation

Denlinger, Robert H.; Anthony, Douglas C.; Amarnath, Kalyani; Amarnath, V.; Graham, Doyle G.

doi:10.1006/taap.1994.1008

Cited by 14 publications

(8 citation statements)

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“…In fact, the unexpected result that MMI instead increased these neurotoxic effects of HOIDPN, described here for the first time, indicates that HOIDPN either is the active metabolite or is further activated by a non-FMO pathway and that FMO metabolism of HOIDPN is a detoxification pathway. Finally, although we cannot exclude the possibility of further enzymatic and/or spontaneous activation of HOIDPN, we find no support for the proposal by Denlinger et al (1994) that the reactive IDPN species is derived from the activation of the bifunctional nitrile groups of the intact molecule.…”

Section: Discussioncontrasting

confidence: 97%

“…Although these workers did not recognize it, their data also support a detoxifying role for the P450-mediated oxidative N-dealkylation of IDPN, which involves rate-limiting C-H bond breaking at C-3. The fact that the P450 reaction produces both /6-aminopropionitrile and cyanoacetaldehyde, the latter being further oxidized to cyanoacetic acid (see Jacobson et al, 1987), explains the later finding by Denlinger et al (1994) that deuteration at the 3-position of IDPN also results in reduced urinary output of cyanoacetic acid.…”

Section: Discussionmentioning

confidence: 99%

“…After observing enhanced vestibular and auditory toxicity of LDPN with CC1 4 pretreatment, Llorens and Crofton (1991) concluded that P450 metabolism is not required to activate IDPN, but instead may define a detoxification pathway. Recent work with deuterated analogs of LDPN suggests that activation of IDPN near the 2-position may be necessary for the behavioral syndrome and peripheral axonopathy (Denlinger et al, 1992(Denlinger et al, , 1994. Genter et al (1994a) conducted a series of studies in which olfactory P450 isoform 2E1 concentrations were manipulated.…”

Section: Icities C 1997 Society Of Tomentioning

confidence: 99%

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Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

et al. 1997

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This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite N-hydroxy3,3'-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long-Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMOmediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotox- icitieS. C 1997 Society of ToThe synthetic organonitrile 3,3'-iminodipropionitrile (IDPN) is known to produce the ECC syndrome excitation with cho-' This article has been reviewed by the National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This work was supported in part by the North Carolina Agricultural Research Service (M.B.G.), NIEHS Grant ES-00044 (M.B.G.), and NIH Grant NS22688 (L.M.S.).2 To whom correspondence should be addressed at Neurotoxicology Division [MD-74B] USEPA, R.T.P., NC 27711. E-mail: crofton.kevin® EPAMAIL.EPA.GOV. reiform and circling movements (Delay, 1952; Thullier and Burger, 1954;Selye, 1957) through degeneration of the vestibular system (Slagel and Hartman, 1965;Llorens et al., 1993;Llorens and Dememes, 1994). IDPN has also been associated with auditory and olfactory damage, and proximal axonopathy (Chou and Hartman, 1964;Griffin et al., 1978;Crofton and Knight, 1991;Genter et al, 1992Genter et al, , 1994aCrofton et al., 1994). Currently, the role of metabolism in IDPNinduced neurotoxicity is unclear.Theories on the activation of LDPN have involved three possible metabolic pathways: (1) cytochrome P450 metabolism, (2) monoamine oxidase (MAO) metabolism, and (3) flavin-containing monooxygenase (FMO) metabolism (e.g., Jacobson et al., 1987). It has also been suggested that IDPN is the toxic compound and needs no hepatic bioactivation (Llorens and Crofton, 1991). Tanii et al. (1984) first demonstrated that the neurotoxicity of some related neurotoxic nitriles (e.g., 2-pentenenitrile) was increased by inactivation of hepatic P450s with carbon tetrachloride (CC1 4 ) pretreatment. After observing enhanced v...

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Section: Discussioncontrasting

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Icities C 1997 Society Of Tomentioning

confidence: 99%

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Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

et al. 1997

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“…The conclusion that protein adduction is a key step in the γ‐diketone and carbon disulphide axonopathies led to the unified theory of pathogenesis that included protein adduction as the common cause of chemically induced axonal neuropathies . The theory included the proposal that IDPN is metabolized to reactive metabolites able to generate protein adducts ; this theory has received some support , but has not been proven. In fact, in contrast to the n‐hexane analogues and carbon disulphide, the mechanism of toxicity of IDPN remains unclear.…”

Section: Mechanisms Underlying Toxic Neurofilamentous Axonopathiesmentioning

confidence: 99%

Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

Llorens

2013

J Intern Med

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A number of neurotoxic chemicals induce accumulation of neurofilaments in axonal swellings that appear at varying distances from the cell body. This pathology is associated with axonal degeneration of different degrees. The clinical manifestation is most commonly that of a mixed motor-sensory peripheral axonopathy with a distoproximal pattern of progression, as in cases of chronic exposure to n-hexane and carbon disulphide. It has been demonstrated that protein adduct formation is a primary molecular mechanism of toxicity in these axonopathies, but how this mechanism leads to neurofilament accumulation and axonal degeneration remains unclear. Furthermore, little is known regarding the mechanisms of neurofilamentous axonopathy caused by 3,3′-iminodipropionitrile, an experimental toxin that induces proximal axon swelling that is strikingly similar to that found in early amyotrophic lateral sclerosis. Here, we review the available data and main hypotheses regarding the toxic axonopathies and compare them with the current knowledge of the biological basis of neurofilament transport. We also review recent studies addressing the question of how these axonopathies may cause axonal degeneration. Understanding the mechanisms underlying the toxic axonopathies may provide insight into the relationship between neurofilament behaviour and axonal degeneration, hopefully enabling the identification of new targets for therapeutic intervention. Because neurofilament abnormalities are a common feature of many neurodegenerative diseases, advances in this area may have a wider impact beyond toxicological significance.

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“…Finally, it is also known that IDPN is metabolized in the body to a toxic metabolite that in turn exerts its toxic effect [57–59]. Drugs that interfere with IDPN metabolism have been shown to modify IDPN‐induced neurotoxicity [60–62].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Hydrocortisone on Iminodipropionitrile‐Induced Neurotoxicity in Rats

Tariq

Khan

Siddiquei

et al. 2007

Basic Clin Pharma Tox

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Occupational and environmental exposure of synthetic nitriles is of potential relevance to human health. Iminodipropionitrile (IDPN), a prototype nitrile toxin, has been shown to produce dyskinetic syndrome in rodents. This study reports the effect of concomitant exposure of rats to hydrocortisone and IDPN on behavioural abnormalities namely excitation, circling and chorea (ECC) syndrome. Four groups of female Wistar rats were given hydrocortisone (0, 10, 30 and 60 mg/kg, gavage, for 10 days) 30 min. before IDPN (100 mg/kg, intraperitoneally for 8 days). Two additional groups of rats were treated with either saline (control group) or 60 mg/kg of hydrocortisone (drug alone group). The animals were observed for neurobehavioural abnormalities including dyskinetic head movement, circling, tail hanging, air righting reflex and contact inhibition of righting reflex. After behavioural studies, the animals were killed, and the discrete brain regions and temporal bones were collected for biochemistry and inner ear histopathology, respectively. Hydrocortisone significantly and dose dependently attenuated the incidence and severity of IDPN-induced behavioural syndrome. Administration of hydrocortisone (60 mg/kg) alone significantly increased glutathione (GSH) levels in olfactory bulb and striatum, whereas IDPN alone significantly reduced GSH levels in olfactory bulb, striatum and hippocampus. Hydrocortisone (60 mg/kg) significantly compensated IDPN-induced depletions of GSH in different brain regions. Hydrocortisone also protected the animals against IDPN-induced vestibular hair cell degeneration. The protective effect of hydrocortisone may be attributed to its anti-inflammatory and antioxidant properties.

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Metabolism of 3,3′-Iminodipropionitrile and Deuterium-Substituted Analogs: Potential Mechanisms of Detoxification and Activation

Cited by 14 publications

References 0 publications

Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

Toxic neurofilamentous axonopathies– accumulation of neurofilaments and axonal degeneration

Protective Effect of Hydrocortisone on Iminodipropionitrile‐Induced Neurotoxicity in Rats

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