The Experts below are selected from a list of 93 Experts worldwide ranked by ideXlab platform
Alberto Bindoli - One of the best experts on this subject based on the ideXlab platform.
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induction of mitochondrial permeability transition by auranofin a gold i Phosphine Derivative
British Journal of Pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
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Induction of mitochondrial permeability transition by auranofin, a Gold(I)‐Phosphine Derivative
British journal of pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
Maria Pia Rigobello - One of the best experts on this subject based on the ideXlab platform.
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induction of mitochondrial permeability transition by auranofin a gold i Phosphine Derivative
British Journal of Pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
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Induction of mitochondrial permeability transition by auranofin, a Gold(I)‐Phosphine Derivative
British journal of pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
Donald J. Darensbourg - One of the best experts on this subject based on the ideXlab platform.
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Acrylic Acid Derivatives of Group 8 Metal Carbonyls: A Structural and Kinetic Study
2016Co-Authors: Samuel J. Kyran, Andrew D. Yeung, Ashfaq A. Bengali, Donald J. DarensbourgAbstract:The synthesis, spectroscopic, and X-ray structural studies of acrylic acid complexes of iron and ruthenium tetracarbonyls are reported. In addition, the deprotonated η2-olefin bound acrylic acid Derivative of iron as well as its alkylated species were fully characterized by X-ray crystallography. Kinetic data were determined for the replacement of acrylic acid, acrylate, and methylacrylate for the group 8 metal carbonyls by triphenylPhosphine. These processes were found to be first-order in the concentration of metal complex with the rates for dissociative loss of the olefinic ligands from ruthenium being much faster than their iron analogues. However, the ruthenium Derivatives afforded formation of primarily mono-Phosphine metal tetracarbonyls, whereas the iron complexes led largely to trans-di-Phosphine tricarbonyls. This difference in behavior was ascribed to a more stable spin crossover species 3Fe(CO)4 which undergoes rapid CO loss to afford the bis Phosphine Derivative. The activation enthalpies for dissociative loss of the deprotonated η2-bound acrylic acid ligand were found to be larger than their corresponding values in the protonated Derivatives. For example, for dissociative loss of the protonated and deprotonated acrylic acid Derivatives of iron(0) the ΔH⧧ values determined were 28.0 ± 1.2 and 34.1 ± 1.5 kcal·mol–1, respectively. Density functional theory (DFT) computations of the bond dissociation energies (BDEs) in these acrylic acids and closely related complexes were in good agreement with enthalpies of activation for these ligand substitution reactions, supportive of a dissociative mechanism for olefin displacement. Processes related to catalytic production of acrylic acid from CO2 and ethylene are considered
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Acrylic acid Derivatives of group 8 metal carbonyls: a structural and kinetic study.
Inorganic Chemistry, 2013Co-Authors: Samuel J. Kyran, Andrew D. Yeung, Ashfaq A. Bengali, Donald J. DarensbourgAbstract:The synthesis, spectroscopic, and X-ray structural studies of acrylic acid complexes of iron and ruthenium tetracarbonyls are reported. In addition, the deprotonated η2-olefin bound acrylic acid Derivative of iron as well as its alkylated species were fully characterized by X-ray crystallography. Kinetic data were determined for the replacement of acrylic acid, acrylate, and methylacrylate for the group 8 metal carbonyls by triphenylPhosphine. These processes were found to be first-order in the concentration of metal complex with the rates for dissociative loss of the olefinic ligands from ruthenium being much faster than their iron analogues. However, the ruthenium Derivatives afforded formation of primarily mono-Phosphine metal tetracarbonyls, whereas the iron complexes led largely to trans-di-Phosphine tricarbonyls. This difference in behavior was ascribed to a more stable spin crossover species 3Fe(CO)4 which undergoes rapid CO loss to afford the bis Phosphine Derivative. The activation enthalpies for...
Rita Boscolo - One of the best experts on this subject based on the ideXlab platform.
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induction of mitochondrial permeability transition by auranofin a gold i Phosphine Derivative
British Journal of Pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
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Induction of mitochondrial permeability transition by auranofin, a Gold(I)‐Phosphine Derivative
British journal of pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
Guido Scutari - One of the best experts on this subject based on the ideXlab platform.
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induction of mitochondrial permeability transition by auranofin a gold i Phosphine Derivative
British Journal of Pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.
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Induction of mitochondrial permeability transition by auranofin, a Gold(I)‐Phosphine Derivative
British journal of pharmacology, 2002Co-Authors: Maria Pia Rigobello, Guido Scutari, Rita Boscolo, Alberto BindoliAbstract:Gold(I)-thiolate drugs are compounds that specifically interact with thiol and/or selenol groups and are essentially utilized in the treatment of rheumatoid arthritis. Considering the importance of thiol groups in regulating mitochondrial membrane permeability, the effects of auranofin (S-triethylPhosphinegold(I)-2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside), a second-generation gold drug, were studied on mitochondria isolated from rat liver. Auranofin, at submicromolar concentrations, was able to induce the mitochondrial membrane permeability transition observed as swelling and loss of membrane potential. Both events are completely inhibited by cyclosporin A, the specific inhibitor of mitochondrial permeability transition. Calcium ions and energization by succinate are required for the occurrence of permeability transition. By interacting with the active site selenol group, auranofin results as an extremely potent inhibitor of mitochondrial thioredoxin reductase, both isolated and in its mitochondrial environment. It is concluded that auranofin, in the presence of calcium ions, is a highly efficient inducer of mitochondrial membrane permeability transition, potentially referable to its inhibition of mitochondrial thioredoxin reductase. Keywords: Auranofin, calcium, gold(I) complexes, mitochondrial permeability transition, selenium, thiol groups, thioredoxin reductase Introduction Gold(I)-thiolate drugs are compounds essentially utilized in the treatment of rheumatoid arthritis (Kean et al., 1997). They have also been tested as anticancer agents (Simon et al., 1981). Their mode of action involves the control of oxidative damage (Grootveld et al., 1990) and inhibition of several enzymes or transcription factors (Handel et al., 1995; Daniel et al., 1995). The molecular mechanism of their inhibitory effects was essentially referred to an interaction with thiol groups with a reactivity depending on the type of ligand associated with the gold (Crooke & Snyder, 1986). A sequential sulfhydryl exchange mechanism was also postulated to explain the cellular distribution of auranofin and related gold complexes (Snyder et al., 1986). However, gold(I) compounds exhibit also a marked and specific reactivity with selenoenzymes such as glutathione peroxidase (GSPx) (Chaudiere & Tappel, 1984), iodothyronine deiodinase type I (Berry et al., 1991), and thioredoxin reductase (Hill et al., 1997; Gromer et al., 1998a, b; Smith et al., 1999), an enzyme recently shown to possess selenium at its catalytic site (Tamura & Stadtman, 1996; Zhong et al., 1998). Considering glutathione peroxidase, gold(I) Derivatives such as aurothiomalate, aurothioglucose and auranofin have been shown to exert their inhibitory action by forming a glutathionate-gold(I)-selenocysteine glutathione peroxidase ternary complex (GPxSe-Au-SG) (Chaudiere & Tappel, 1984; Roberts & Shaw, 1998). Thioredoxin reductase is present in both the cytosol and mitochondria (Rigobello et al., 1998) where exhibits a sequence different from that of the cytosolic isoform but, similarly to the latter enzyme, possess selenium at its active site (Lee et al., 1999). Selenols are able to bind heavy metals more efficiently than thiols (Grootveld et al., 1990) and, therefore, the selenocysteine of thioredoxin reductase appears as the target of organic gold inhibitors (Gromer et al., 1998a; Zhong et al., 1998). In previous research, it was demonstrated that the redox state of mitochondrial thiols could control the permeability of the mitochondrial membranes (Bindoli et al., 1997; Kowaltowski et al., 2001). In this respect, the thioredoxin system present in mitochondria might play a critical role (Wudarczyk et al., 1996; Rigobello et al., 1998; Kim et al., 1999). We have previously demonstrated (Rigobello et al., 1999) that 13-cis retinoic acid, an inhibitor of thioredoxin reductase (Schallreuter & Wood, 1989) is very effective in inducing mitochondrial permeability transition and release of cytochrome c. Similar effects on mitochondrial membranes permeability increase were observed with arsenite and arsenicals, heavy and transition metal cations, quinones, alloxan and sulfhydryl reagents (Gunter & Pfeiffer, 1990; Zoratti & Szabo, 1995; Sakurai et al., 2001) that are also inhibitors or substrates of thioredoxin reductase. In the latter case they act as electron acceptors (Arner et al., 1999), therefore, diverting electrons from thioredoxin reductase that are no longer fed to its natural substrate, thioredoxin. In the present paper we report evidence that auranofin is a potent inducer of mitochondrial permeability transition possibly referable to its interaction with the mitochondrial isoform of thioredoxin reductase.