Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram

Kitson, Trevor M.

doi:10.1042/bj2130551

Cited by 49 publications

(20 citation statements)

References 16 publications

(24 reference statements)

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“…Indeed, contrary to aldehyde dehydrogenase, NAT1 does not possess two vicinal thiols in its active site [36] and cannot thus be inhibited by the DS‐dependent formation of an intramolecular mixed disulfide [3]. Therefore, the DS‐dependent inhibition of NAT1 is probably the result of the formation of a stable DS adduct that could be inaccessible to displacement by thiol reagents [37]. Cisplatin, an anticancer drug, has been reported recently to irreversibly inhibit NAT1 ( k i = 700 m −1 ·min −1 ) in vivo and in vitro .…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

et al. 2009

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Disulfiram has been used for decades to treat alcoholism. Its therapeutic effect is thought to be mediated by the irreversible inhibition of aldehyde dehydrogenase. Recent reports have indicated new therapeutic uses of disulfiram, in particular in human cancers. Although the biochemical mechanisms that underlie these effects remain largely unknown, certain enzymes involved in cancer processes have been reported to be targeted by disulfiram. Arylamine N‐acetyltransferase 1 (NAT1) is a xenobiotic‐metabolizing enzyme that biotransforms aromatic amine drugs and carcinogens. In addition to its role in xenobiotic metabolism, several studies have suggested that NAT1 is involved in other physiological and/or pathological processes, such as folate metabolism or cancer progression. In this report, we provide evidence that human NAT1 is a new enzymatic target of disulfiram. We found that disulfiram at clinically relevant concentrations impairs the activity of endogenous NAT1 in human cancer cells. Further mechanistic and kinetic studies indicated that disulfiram reacts irreversibly with the active site cysteine residue of NAT1, leading to its rapid inhibition (IC50 = 3.3 ± 0.1 μm and ki = 6 × 104 m−1·min−1).

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Section: Discussionmentioning

confidence: 99%

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

et al. 2009

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“…Disulfiram, as used in the aversion therapy of recovering alcoholics, is described to react specifically with human liver aldehyde dehydrogenase (ALDH) E1 with a loss of catalytic activity and without incorporation (DDTC is formed and the number of enzyme thiol groups decreases during this process) [74]. However, incorporation could be detected within the first few minutes when ALDH was inhibited by disulfiram [75]. It seems that the ALDH inhibition by disulfiram is caused by the formation of an intramolecular disulfide bond between the active site thiol and the thiol of another cysteine residue [76][77].…”

Section: General Biological Activity Of Dithiocarba-matesmentioning

confidence: 98%

Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals

Cvek

Dvořák²

2007

CPD

132

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Dithiocarbamates and their complexes with transition metals have been used as common pesticides, vulcanizing or analytical agents for decades. These compounds are one of the most reported inhibitors of nuclear factor-kappaB (NF-kappaB) signaling cascade. Recently, it has been found that dithiocarbamates are very potent inhibitors of proteasome. NF-kappaB plays a central role in the immune system and is described as a major actor in many of human cancers mainly because of its protective effects against apoptosis. Molecular mechanisms involved in regulation and function of NF-kappaB pathway have been elucidated recently. In particular, pivotal zinc containing proteins that alter NF-kappaB signal transduction were recognized. Additionally, proteasome system was found to be a key player in NF-kappaB pathway and is an attractive target for anticancer drug development. Collectively, the capability of dithiocarbamates to inhibit NF-kappaB and proteasome makes these compounds promising anticancer agents. This review focuses on the biological activity of dithiocarbamate coordination compounds with regard to their possible molecular targets in NF-kappaB signaling and proteasome (JAMM domain proteins). Future research should aim to find the most suitable dithiocarbamate coordination compounds for treatment of cancer and other diseases.

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“…DTDS and DDTC also inhibit aldehyde dehydrogenase in the liver and erythrocytes [15][16][17]. DTDS inhibits other enzymes, such as fructose 1,6-diphosphate dehydrogenase and succinate dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFκB c-fos/c-jun, and p53 proteins

et al. 1998

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Prolinedithiocarbamate (PDTC) and diethyldithiocarbamate (DDTC) are cancer chemopreventive agents and can be biotransformed to prolinethiuramdisulfide (PTDS) and tetraethylthiuramdisulfide (disulfiram; DTDS), respectively. We found that the reactive metabolites PTDS and DTDS induced apoptosis after G1/S arrest. Phosphorylation of cyclin E, inhibition of cyclin-dependent kinase 2 activity, and degradation of cyclin E were found in human hepatoma Hep G2 cells during apoptosis. Moreover, PTDS and DTDS decreased the level of bcl-2 but increased the level of p53. In contrast, PDTC, DDTC, and ammonium dithiocarbamate (ADTC) did not induce apoptosis; rather they led to the induction of p53 and p21 followed by G1/S arrest. PDTC, DDTC, and ADTC also arrested cells in G1 phase. We then examined the effects of PTDS and DTDS on the signal transduction mechanisms leading to apoptosis. Although the transcription factors NFkappaB and AP-1 cooperatively decreased their DNA-binding activities to kappaB and 12-O-tetradecanoylphorbol-13-acetate-responsive elements, respectively, and p53 increased DNA-binding activity in the early stage but decreased it in the latter stage after treatment with PTDS, when the human Hep G2 cells were undergoing apoptosis. In summary, our results indicated that (i) PTDS and DTDS induced apoptosis and G1/S arrest mediated by p53, whereas PDTC, DDTC, and ADTC induced p53-dependent p21 expression leading to G1/S arrest; (ii) PDTC, DDTC, and ADTC induced p21/KIP1/CIP1 expression in a p53-dependent pathway leading to G1/S arrest; and (iii) NFkappaB, AP-1, and bcl-2 were downregulated during PTDS- and DTDS-induced apoptosis. These results suggested that PTDS and DTDS induced p53-dependent apoptosis, whereas PDTC, DDTC, and ADTC induced G1/S arrest. Apoptosis is regulated by the modulation of intracellular effectors such as NFkappaB, AP-1, and bcl-2 and activation of p53 in early stages.

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Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram

Cited by 49 publications

References 16 publications

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals

Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFκB c-fos/c-jun, and p53 proteins

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Mechanism of inactivation of sheep liver cytoplasmic aldehyde dehydrogenase by disulfiram

Cited by 49 publications

References 16 publications

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

Mechanisms and kinetics of human arylamine N‐acetyltransferase 1 inhibition by disulfiram

Targeting of Nuclear Factor-&#954;B and Proteasome by Dithiocarbamate Complexes with Metals

Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFκB c-fos/c-jun, and p53 proteins

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Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals