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Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.
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doi:10.4269/ajtmh.14-0029 Copyright © 2014 by The American Society of Tropical Medicine and Hygiene
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:Abstract. In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95 % and 64 % total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction. Schistosomiasis is a neglected but widespread tropical disease caused by infection with parasitic blood flukes. Schistosoma mansoni,Schistosomahaematobium, andSchistosoma japonicum are the most widely distributed species and cause the highest disease burden, particularly in sub-Saharan Africa.1–3 Prazi-quantel (PZ) is the only drug available for treatment of this dis-ease, and it is active against adult schistosomes, but has littl
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antischistosomal versus antiandrogenic properties of aryl hydantoin ro 13 3978
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.
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activity of antiandrogens against juvenile and adult schistosoma mansoni in mice
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Mireille Vargas, Jennifer Keiser, Jonathan L VennerstromAbstract:Objectives The antischistosomal properties of the marketed antiandrogens bicalutamide, flutamide, Nilutamide and cyproterone acetate were studied both in vivo and in vitro. Methods Schistosoma mansoni-infected mice were treated orally with 50-400 mg/kg of the antiandrogens 3 and 7 weeks post-infection. In addition, three drug combinations of Nilutamide and praziquantel (200/100, 100/100 and 100/50 mg/kg) were administered to mice harbouring adult S. mansoni. Drug effects were also monitored in vitro following exposure to antiandrogen concentrations of 1, 10 and 100 microg/mL. Results Low total worm burden reductions (5%-37%) and low to moderate female worm burden reductions (13%-75%) were achieved with the antiandrogens in the S. mansoni juvenile infection model. While flutamide and cyproterone acetate lacked activity against adult S. mansoni in vivo, low to moderate total and female worm burden reductions (0%-47%) were observed with bicalutamide. The highest total and female worm burden reductions (85% and 71%, respectively) (P > 0.001) were documented following a single 400 mg/kg dose of Nilutamide. Statistically significant total (91%) and female (85%) worm burden reductions were achieved with the combination of Nilutamide (200 mg/kg) and praziquantel (100 mg/kg). Schistosomes incubated with 100 microg/mL cyproterone acetate in vitro died after 15 h. Incubation with bicalutamide, Nilutamide and flutamide at 100 microg/mL resulted in decreased movement of S. mansoni adults. Conclusions Our data indicate that the hydantoin derivative Nilutamide has interesting antischistosomal properties, confirming previous results of schistosomicidal activities of this drug class
Mireille Vargas - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug Nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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doi:10.4269/ajtmh.14-0029 Copyright © 2014 by The American Society of Tropical Medicine and Hygiene
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:Abstract. In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95 % and 64 % total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction. Schistosomiasis is a neglected but widespread tropical disease caused by infection with parasitic blood flukes. Schistosoma mansoni,Schistosomahaematobium, andSchistosoma japonicum are the most widely distributed species and cause the highest disease burden, particularly in sub-Saharan Africa.1–3 Prazi-quantel (PZ) is the only drug available for treatment of this dis-ease, and it is active against adult schistosomes, but has littl
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Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K ChiuAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug Nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins
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antischistosomal versus antiandrogenic properties of aryl hydantoin ro 13 3978
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.
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activity of antiandrogens against juvenile and adult schistosoma mansoni in mice
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Mireille Vargas, Jennifer Keiser, Jonathan L VennerstromAbstract:Objectives The antischistosomal properties of the marketed antiandrogens bicalutamide, flutamide, Nilutamide and cyproterone acetate were studied both in vivo and in vitro. Methods Schistosoma mansoni-infected mice were treated orally with 50-400 mg/kg of the antiandrogens 3 and 7 weeks post-infection. In addition, three drug combinations of Nilutamide and praziquantel (200/100, 100/100 and 100/50 mg/kg) were administered to mice harbouring adult S. mansoni. Drug effects were also monitored in vitro following exposure to antiandrogen concentrations of 1, 10 and 100 microg/mL. Results Low total worm burden reductions (5%-37%) and low to moderate female worm burden reductions (13%-75%) were achieved with the antiandrogens in the S. mansoni juvenile infection model. While flutamide and cyproterone acetate lacked activity against adult S. mansoni in vivo, low to moderate total and female worm burden reductions (0%-47%) were observed with bicalutamide. The highest total and female worm burden reductions (85% and 71%, respectively) (P > 0.001) were documented following a single 400 mg/kg dose of Nilutamide. Statistically significant total (91%) and female (85%) worm burden reductions were achieved with the combination of Nilutamide (200 mg/kg) and praziquantel (100 mg/kg). Schistosomes incubated with 100 microg/mL cyproterone acetate in vitro died after 15 h. Incubation with bicalutamide, Nilutamide and flutamide at 100 microg/mL resulted in decreased movement of S. mansoni adults. Conclusions Our data indicate that the hydantoin derivative Nilutamide has interesting antischistosomal properties, confirming previous results of schistosomicidal activities of this drug class
Chunkai Wang - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug Nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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doi:10.4269/ajtmh.14-0029 Copyright © 2014 by The American Society of Tropical Medicine and Hygiene
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:Abstract. In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95 % and 64 % total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction. Schistosomiasis is a neglected but widespread tropical disease caused by infection with parasitic blood flukes. Schistosoma mansoni,Schistosomahaematobium, andSchistosoma japonicum are the most widely distributed species and cause the highest disease burden, particularly in sub-Saharan Africa.1–3 Prazi-quantel (PZ) is the only drug available for treatment of this dis-ease, and it is active against adult schistosomes, but has littl
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Revisiting the SAR of the Antischistosomal Aryl Hydantoin (Ro 13-3978)
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K ChiuAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug Nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimization of antischistosomal hydantoins
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antischistosomal versus antiandrogenic properties of aryl hydantoin ro 13 3978
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.
Yuxiang Dong - One of the best experts on this subject based on the ideXlab platform.
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revisiting the sar of the antischistosomal aryl hydantoin ro 13 3978
Journal of Medicinal Chemistry, 2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Jeremy O Jones, Karen L White, David M Shackleford, Gong Chen, Jessica Saunders, Francis C K Chiu, Yuxiang DongAbstract:The aryl hydantoin 1 (Ro 13-3978) was identified in the early 1980s as a promising antischistosomal lead compound. However, this series of aryl hydantoins produced antiandrogenic side effects in the host, a not unexpected outcome given their close structural similarity to the antiandrogenic drug Nilutamide. Building on the known SAR of this compound series, we now describe a number of analogs of 1 designed to maximize structural diversity guided by incorporation of substructures and functional groups known to diminish ligand–androgen receptor interactions. These analogs had calculated polar surface area (PSA), measured LogD7.4, aqueous kinetic solubility, and estimated plasma protein binding values in ranges predictive of good ADME profiles. The principal SAR insight was that the hydantoin core of 1 is required for high antischistosomal activity. We identified several compounds with high antischistosomal efficacy that were less antiandrogenic than 1. These data provide direction for the ongoing optimizati...
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doi:10.4269/ajtmh.14-0029 Copyright © 2014 by The American Society of Tropical Medicine and Hygiene
2016Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:Abstract. In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95 % and 64 % total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction. Schistosomiasis is a neglected but widespread tropical disease caused by infection with parasitic blood flukes. Schistosoma mansoni,Schistosomahaematobium, andSchistosoma japonicum are the most widely distributed species and cause the highest disease burden, particularly in sub-Saharan Africa.1–3 Prazi-quantel (PZ) is the only drug available for treatment of this dis-ease, and it is active against adult schistosomes, but has littl
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antischistosomal versus antiandrogenic properties of aryl hydantoin ro 13 3978
American Journal of Tropical Medicine and Hygiene, 2014Co-Authors: Chunkai Wang, Qingjie Zhao, Mireille Vargas, Yuxiang Dong, Xiaofang Wang, Jaeki Min, Sakthivel Muniyan, Kiplin R Guy, Mingfong Lin, Jennifer KeiserAbstract:In the early 1980s, the antischistosomal aryl hydantoin Ro 13-3978 (AH01), a close structural analogue of the androgen receptor antagonist Nilutamide, was discovered. Administration of 100 mg/kg oral doses of AH01 to mice infected with adult and juvenile Schistosoma mansoni produced 95% and 64% total worm burden reductions, confirming its high activity against adult worms, and showing that AH01 is also effective against juvenile infections. AH01 had no measureable interaction with the androgen receptor in a ligand competition assay, but it did block dihydrotestosterone-induced cell proliferation in an androgen-dependent human prostate cancer cell line. For AH01, Nilutamide, and three closely related aryl hydantoin derivatives, there was no correlation between antischistosomal activity and androgen receptor interaction.
Dominique Pessayre - One of the best experts on this subject based on the ideXlab platform.
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inhibition by Nilutamide of the mitochondrial respiratory chain and atp formation possible contribution to the adverse effects of this antiandrogen
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Alain Berson, Daniel Fau, Bernard Fromenty, C Fisch, L Schmets, Claude Wolf, D Deschamps, Dominique PessayreAbstract:The effects of Nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, Nilutamide (100 microM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I occurred without any lag time. In submitochondrial particles, Nilutamide (100 microM) decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the Nilutamide nitro anion free radical by submitochondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Severe inhibition of complex I by Nilutamide (500 microM) led to upstream inhibition of fatty acid beta-oxidation. Nilutamide (100 microM) decreased the mitochondrial membrane potential and ATP formation in mitochondria energized by malate plus glutamate. In hepatocytes incubated without glucose, Nilutamide (500 microM) led to an early (2 hr) drop in cellular ATP and early (4 hr) toxicity. With 5 mM glucose, however, ATP was not decreased and toxicity was mild at these early times. It was concluded that Nilutamide itself inhibited the mitochondrial respiratory chain at the level of complex I and decreased ATP in hepatocytes incubated without glucose, which resulted in early toxicity. In the presence of glucose, ATP was not depleted at early times and delayed toxicity was probably the result of an oxidative stress (as previously reported).
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interest of esr in determining the mechanisms of drug toxicity application to the antiandrogen Nilutamide
Journées européennes sur l'application de la RPE aux matériaux organiques biologiques et bio organiques, 1994Co-Authors: Alain Berson, Daniel Fau, Claude Wolf, C Chachaty, Dominique PessayreAbstract:Le Nilutamide est un andiandrogene ayant la structure d'un nitroarene qui est utilise dans le traitement du cancer de la prostate metastase. Les effets secondaires du Nilutamide comprennent des hepatites aigues et des fibroses pulmonaires interstitielles. En utilisant la RPE, nous avons montre que la NADPH-cytochrome P-450 utilisant la RPE, nous avons montre que la NADPH-cytochrome P-450 reductase catalyse la reduction monoelectronique du Nilutamide en un radical anion nitro dans les microsomes hepatiques et pulmonaires de rat
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Printed ¡nU.S.A. Inhibition by Nilutamide of the Mitochondrial Respiratory Chain and ATP Formation. Possible Contribution to the Adverse Effects of This Antiandrogen1
1994Co-Authors: Alain Berson, Daniel Fau, Bernard Fromenty, L Schmets, Claude Wolf, D Deschamps, Cecile Fisch, Dominique PessayreAbstract:The effects of Nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, Nilutamide (100 MM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I oc curred without any lag time. In submitochondrial particles, nilu tamide (100 /¿M)decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of Superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the Nilutamide nitro aniÃn free radical by submito chondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Sever
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mechanism for the hepatotoxicity of the antiandrogen Nilutamide evidence suggesting that redox cycling of this nitroaromatic drug leads to oxidative stress in isolated hepatocytes
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: Daniel Fau, Alain Berson, D Eugene, Bernard Fromenty, C Fisch, Dominique PessayreAbstract:The nitroaromatic drug Nilutamide has been shown previously to undergo redox cycling in aerobic rat liver microsomes, being reduced by NADPH-cytochrome P-450 reductase to a nitro anion-free radical which reacts with oxygen, to regenerate the parent drug, and form a superoxide anion dismuted to hydrogen peroxide. In the present study, the effects of Nilutamide on isolated rat hepatocytes have been determined. After 6 and 8 hr of incubation with 0.5 mM Nilutamide, lactate dehydrogenase was released in the incubation medium, and cell viability was decreased markedly. Consistent with a redox cycle producing reactive oxygen species, Nilutamide increased nonmitochondrial (cyanide-resistant) oxygen consumption; the toxicity of Nilutamide occurred sooner and was more extensive in the presence of sodium azide (an inhibitor of catalase). Consistent with an oxidative stress, the toxicity of Nilutamide was associated with depletion of reduced glutathione, increased levels of glutathione disulfide, increased Ca(++)-dependent phosphorylase a activity, oxidation and accumulation of cytoskeleton-associated proteins and formation of blebs; toxicity was prevented by glutathione precursors, thiol reductants and/or antioxidants, such as L-cystine, L-cysteine, N-acetyl-L-cysteine, dithiothreitol, N,N'-diphenyl-p-phenylene-diamine and alpha-tocopherol. Feeding the animals with a diet supplemented with 2% L-cystine increased the initial glutathione stores of hepatocytes and prevented Nilutamide toxicity. It is concluded that Nilutamide is toxic to isolated rat hepatocytes, as a probable consequence of an oxidative stress due to the redox cycling of this nitroaromatic compound.
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generation of free radicals during the reductive metabolism of Nilutamide by lung microsomes possible role in the development of lung lesions in patients treated with this anti androgen
Biochemical Pharmacology, 1992Co-Authors: Virginie Berger, Daniel Fau, Alain Berson, Bernard Fromenty, Claude Wolf, Claude Chachaty, Dominique PessayreAbstract:Abstract The pulmonary metabolism of Nilutamide, a nitroaromatic anti-androgen drug leading to pulmonary lesions in a few recipients, has been investigated in rats. Incubation of Nilutamide (1 mM) with rat lung microsomes and NADPH under anaerobic conditions led to the formation of the nitro anion free radical, as indicated by ESR spectroscopy. The steady state concentration of this radical was not decreased by CO or SKF 525-A (two inhibitors of cytochrome P450), but was decreased by NADP + (10 mM) or p -chloromercuribenzoate (0.47 mM) (two inhibitors of NADPH-cytochrome P450 reductase activity). Anaerobic incubations of [ 3 H]Nilutamide (0.1 mM) with rat lung microsomes and a NADPH-generating system resulted in the in vivo covalent binding of [ 3 H]Nilutamide metabolites to microsomal proteins; covalent binding required NADPH; it was decreased in the presence of NADP + (10 mM), or in the presence of the nucleophile glutathione (10 mM), but was unchanged in the presence of carbon monoxide. Under aerobic conditions, in contrast, the nitro anion free radical was reoxidized by oxygen, and its ESR signal was not detected. Covalent binding was essentially suppressed. Instead, there was consumption of NADPH and oxygen, and production of Superoxide anion and hydogen peroxide. We conclude that Nilutamide is reduced by rat lung microsomes NADPH-cytochrome P450 reductase into a nitro anion free radical. In anaerobiosis, the radical is reduced further to covalent binding species. In the presence of oxygen, in contrast, this nitro anion free radical undergoes redox cycling, with the generation of reactive oxygen species.