In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by s-methyl N, N-diethylthiolcarbamate sulfoxide, a new metabolite of disulfiram

Hart, Bruce W.; Faiman, Morris D.

doi:10.1016/0006-2952(92)90555-w

Cited by 77 publications

(62 citation statements)

References 7 publications

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“…31 Previous investigations of the activity of both DSF and other DTC derivatives have focused on biotransformations of the DTC ligand itself, but little consideration was given to what effect metal-uptake might induce. 11,12,15,16 The toxicity of dithiocarbamates such as pDTC have been attributed to a Cu-catalyzed intracellular conversion to a tetraalkylthiuram disulfide (e.g. DSF), which can then disrupt the redox homeostasis within the cell.…”

Section: Discussionmentioning

confidence: 99%

“…Our evidence points to the Cu(deDTC) 2 complex as the active form, but how it then induces the strong apoptotic response remains obscure. In this regard, sulfur oxygenation and extrusion have been proposed as modes of the xenobiotic activation of DSF 11,12 and also as possible sources of its neurotoxicity. 32 We have recently shown that similar sulfur oxygenation and extrusion may occur within a metal-DTC complex.…”

Section: Discussionmentioning

confidence: 99%

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Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells

et al. 2004

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The alcohol-abuse deterrent disulfiram (DSF) is shown to have a highly selective toxicity against melanoma in culture, inducing a largely apoptotic response, with much lower toxicity against several other cell lines. Melanoma cell lines derived from different stages (radial, vertical, and metastatic phase) were all sensitive to DSF treatment in vitro; melanocytes were only slightly affected. A required role of extracellular Cu is demonstrated for DSF toxicity. Low concentrations of DSF alone decreased the number of viable cells, and the addition of CuCl2 significantly enhanced the DSF-induced cell death to less than 10% of control. Significantly, the intracellular Cu concentration of melanoma cells increased rapidly upon DSF treatment. Both the intracellular Cu uptake and the toxicity induced by DSF were blocked by co-incubation with bathocuproine disulfonic acid (BCPD, 100 μM), a non-membrane-permeable Cu chelator. Chemical studies demonstrated a complicated, extracellular redox reaction between Cu(II) and DSF, which forms the complex Cu(deDTC)2 in high yield, accompanied by oxidative decomposition of small amounts of disulfiram. The Cu complex has somewhat higher activity against melanoma and is suggested to be the active agent in DSF-induced toxicity. The redox conversion of DSF was unique to Cu(II) and not engendered by the other common biological metal ions Fe(II or III), Mn(III), and Zn(II). The implications of this work are significant both in the possible treatment of melanoma as well as in limiting the known side-effects of DSF, which we propose may be diminished by cotreatment to decrease adventitious Cu.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells

et al. 2004

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“…§ Authors to whom correspondence should be addressed: (14). Carbamoylated glutathione, S-(N,N-diethylcarbamoyl)-glutathione (DETC-GS), was prepared essentially as described by Jin et al (10).…”

Section: Animals-malementioning

confidence: 99%

“…A QE300 NMR spectrometer (General Electric, Fremont, CA) and Autospec-Q tandem hybrid mass spectrometer (Fiscons/VG Analytical Limited, Manchester, United Kingdom) were employed for these analyses. Liver aldehyde dehydrogenase was extracted and assayed as described previously (14). MetSOX, monosodium L-glutamate, glycine, glutathione, and NMDA were purchased from Sigma.…”

Section: Animals-malementioning

confidence: 99%

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

Nagendra¹,

Faiman²,

Davis³

et al. 1997

Journal of Biological Chemistry

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Considerable effort has been devoted to discovery of glutamate antagonists (1, 2) in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders (3). Unfortunately, while known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects (1, 2). To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy (4). Unlike classical antagonists, that can give complete inhibition by interaction at the glutamate receptor (e.g. CGS 19755) or directly at receptor-linked, calcium ion channels (e.g. phencyclidine or MK-801) (2), inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism (4). At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) 1 (9) that is a potent and selective carbamoylating agent for sulfhydryl groups (10). We now report that DETC-MeSO also partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen. MATERIALS AND METHODS Animals-MaleSwiss Webster mice (20 -30 g) or male SpragueDawley rats (250 -300 g) were used in the study. All experiments that employed animals were conducted in strict compliance with the National Institutes of Health guidelines on animal use and institutional regulations concerning animal experimentation. Animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as described previously (11, 12). The time to first clonic-tonic seizure after bringing animals to a final pressure of 5 atmospheres of 100% oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously (11, 12). Unless otherwise specified, the ability of DETC-MeSO to prevent seizures was tested by intraperitoneal injection of 5.2 mg/kg DETC-MeSO 1-2 h prior to bringing the animal to a final pressure of 5 atmospheres of 100% oxygen or intraperitoneal injection of N-methyl-D-aspartate (NMDA) (125 mg/kg) or L-methionine sulfoximine (MetSOX) (250 mg/kg). Evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of DETC-MeSO was conducted by use of the program GraphPAD InStat from GraphPAD Software (San Diego, CA).Binding Studies-Synap...

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“…Studies from our laboratory showed that DSF must be bioactivated to form a metabolite believed to be responsible for ADLH 2 inhibition [8]. It was also shown that DSF elicits antialcohol effect in vivo only after cytochrome P450 enzymes mediated bioactivation to its active metabolite, DETC-MeSO [21].…”

mentioning

confidence: 99%

S-Methyl-N,N-Diethylthiocarbamate Sulfoxide Elicits Neuroprotective Effect against N-Methyl-<i>D</i>-Aspartate Receptor-Mediated Neurotoxicity

Ningaraj¹,

Chen²,

Schloss³

et al. 2001

J Biomed Sci

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Glutamatergic neurotransmission, particularly of the NMDA receptor type, has been implicated in the excitotoxic response to several external and internal stimuli. In the present investigation, we report that S-methyl-N,N-diethylthiocarbamate sulfoxide (DETC-MeSO) selectively and specifically blocks the NMDA receptor subtype of the glutamate receptors, and attenuates glutamate-induced neurotoxicity in rat-cultured primary neurons. Other major ionotropic glutamate receptor subtypes, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate, were insensitive to DETC-MeSO both in vitro and in vivo. Disulfiram, the parent compound of DETC-MeSO, also inhibits glutamate receptors partially in vivo; however, it fails to inhibit glutamate receptors in mice pretreated with N-butyl imidazole, a cytochrome P450 enzyme inhibitor, implicating the need for bioactivation of disulfiram to be an effective antagonist. We showed that glutamate-induced increase in ⁴⁵Ca²⁺ was attenuated in rat-cultured primary neurons following pretreatment with DETC-MeSO. The Ca²⁺ influx into primary neurons, studied by confocal microscopy of the fluorescent Ca²⁺dye fura-2, demonstrated a complete attenuation of NMDA-induced Ca²⁺ influx. Similarly, DETC-MeSO attenuated NMDA-induced ⁴⁵Ca²⁺uptake. Glutamate-induced ⁴⁵Ca²⁺uptake andCa²⁺ influx, however, were partially blocked by DETC-MeSO, and this is consistent with both in vitro and in vivo studies in which DETC-MeSO partially blocked mouse brain glutamate receptors. In addition, DETC-MeSO pretreatment effectively prevented seizures in mice induced either by NMDA, ammonium acetate, or ethanol-induced kindling seizures, all of which are believed to be mediated by NMDA receptors. These data demonstrate that DETC-MeSO produces the neuroprotective effect through antagonism of NMDA receptors in vivo.

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In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by s-methyl N, N-diethylthiolcarbamate sulfoxide, a new metabolite of disulfiram

Cited by 77 publications

References 7 publications

Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells

Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

S-Methyl-N,N-Diethylthiocarbamate Sulfoxide Elicits Neuroprotective Effect against N-Methyl-<i>D</i>-Aspartate Receptor-Mediated Neurotoxicity

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