Increased biliary secretion and loss of hepatic glutathione in rat liver after nifurtimox treatment

Dubin, Marta; Moreno, Silvia N.J.; Martino, Elba E.; Docampo, Roberto; Stoppani, A. O. M.

doi:10.1016/0006-2952(83)90527-0

Cited by 32 publications

(2 citation statements)

References 21 publications

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“…Drugs such as aminophenazone, propyphenazone, phenytoin, acetaminophen, morphine, and nitrofurantoin deplete hepatic GSH due to their metabolism with subsequent inactivation of reactive metabolites by GSH conjugation reactions (Aikawa et al 1978;Dubin et al 1983;Correira et al 1984;Bien and Witt 1985;Ekl6w-Lastbom et al 1986;Rossi et al 1988, Roy andSnodgrass 1988). These drugs have no effects in the brain because they possibly do not undergo cerebral metabolism and, therefore, they do not affect the GSH pool.…”

Section: Discussionmentioning

confidence: 95%

Effects of exogenous factors on the cerebral glutathione in rodents

1992

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Since glutathione is thought to be involved in cerebral functions, changes in the glutathione level imply modulations of the neurotransmission in addition to all the known effects of GSH. It was investigated whether alterations of the cerebral glutathione can be induced by consumption of GSH, by inhibition or stimulation of the synthesis of GSH, or by an inhibition of the re-reduction of the oxidized glutathione. Aminophenazone, propyphenazone, acetaminophen, phenytoin, morphine and nitrofurantoin, known to deplete hepatic GSH, had no effects on cerebral GSH. Diethyl maleate (0.6 ml/kg) decreased the cerebral content of GSH and GSSG in adult rats as well as in fetuses. The depletion of the cerebral GSH caused by diethyl maleate treatment for 4 days was followed by an increase up to 125% and a subsequent return to the normal level after 1 week. In rats starved up to 71 h deficiency of exogenous amino acids caused only a minimal or no decrease in cerebral GSH. The specific inhibitor of the gamma-glutamylcysteine synthetase BSO only depleted GSH in the brain of young mice following the repeated s.c. administration of a high dose (890 mg/kg). After cobaltous chloride (20 mg/kg; twice a day for 2 or 4 days) the GSH level in the brain was unchanged. In vivo inhibition of the cerebral glutathione reductase was caused by ammonium metavanadate (12.5 mg/kg; three times a week for 6 weeks). Nitrofurantoin (150 mg/kg) had no effect. After lomustine (10 mg/kg) a minimal increase in glutathione reductase was found, but simultaneously also an increase in GSSG and of the ratio GSSG/total glutathione.

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Section: Discussionmentioning

confidence: 95%

Effects of exogenous factors on the cerebral glutathione in rodents

1992

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“…Evidence of NADPH depletion was seen in previous metabolism studies using DNB. 6 In addition, studies utilizing other nitroaromatics, nitrofurantoin and nifurtimox, have demonstrated that these compounds, through depletion of NADPH, may perturb redox metabolism within the liver, causing the observed increase in GSSG excreted into the bile (29,30). Other experiments indicated that nitrofurantoin treatment increased GSSG concentration through inhibition of GSSG reductase (29).…”

Section: Discussionmentioning

confidence: 99%

1,3-Dinitrobenzene Metabolism and GSH Depletion

Reeve

Voss

Miller

2002

Chem. Res. Toxicol.

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Previous work demonstrated that the mitochondrial fraction of rat seminiferous tubules is capable of metabolizing 1,3-dinitrobenzene, using NADPH as a cofactor. Moreover, 1,3-dinitrobenzene treatment of rat tubules caused a decrease in mitochondrial GSH levels. In situ mitochondrial metabolism of 1,3-dinitrobenzene may have caused this depletion through the production of reactive oxygen intermediates, generating oxidative stress and/or one or more metabolites of 1,3-dinitrobenzene which reacted nonenzymatically with GSH. The goal of this study is to investigate which of these two potential mechanisms may have caused the observed GSH depletion. Liver microsomes, known to rapidly metabolize 1,3-dinitrobenzene, generated the superoxide anion radical when incubated with 1,3-dinitrobenzene and NADPH. However, with the seminiferous tubule mitochondria, no oxygen radicals were detected. Hence, the aforementioned GSH depletion is unlikely due to the production of reactive oxygen intermediates from in situ mitochondrial metabolism of 1,3-dinitrobenzene. To investigate the ability of 1,3-dinitrobenzene metabolites to deplete seminiferous tubule mitochondrial GSH, mitochondria were incubated with 1,3-dinitrobenzene and NADPH. Loss of GSH correlated with the appearance of the 1,3-dinitrobenzene metabolites, nitrophenylhydroxylamine and nitroaniline. Subsequent investigation demonstrated that the metabolites, nitrosonitrobenzene, known to react nonenzymatically with nonprotein sulfhydryls, and nitrophenylhydroxylamine both oxidized seminiferous tubule mitochondrial GSH. Further studies suggested that nitrophenylhydroxylamine could deplete GSH via a free radical mechanism. In aqueous solution, this metabolite was shown to exist in equilibrium with a radical form, thought to be the hydronitroxide radical. The addition of GSH eliminated the signal, implying that the radical reacted nonenzymatically with GSH. In conclusion, the data in this study suggest that the decrease in mitochondrial GSH observed in DNB-treated seminiferous tubules is due to the formation of NPHA and NNB and not reactive oxygen intermediates.

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