Pyrazinamide and disulfiram effects on male rat's reproductive function

Коваленко, В. М.; Bondarenko, Larysa; Byshovetz, T.; Shayakhmetova, Ganna M.; Voronina, A.; Voloshina, O.; Сапрыкина, Н А

doi:10.1016/j.toxlet.2006.07.289

Cited by 3 publications

(3 citation statements)

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“…The stock solutions of high-dose (250 mg ml −1 ) and low-dose (125 mg ml −1 ) were prepared everyday before administration. The low and highdose exceeded the normal human dose (40 mg kg −1 ) by 4-and 8-fold, respectively, 17,18 for efficient model-construction in comparatively short time in rats. After administration of PZA, the rats were observed for recording their behavioral changes.…”

Section: Animals and Drug Administrationmentioning

confidence: 92%

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach

Zhao

et al. 2017

Toxicol. Res.

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Pyrazinamide (PZA) is a well-known first line anti-tuberculosis drug used in combination with other drugs such as isoniazid and rifampicin. Unfortunately, PZA suffered from a high rate of hepatotoxicity and hyperuricemia, which has not been clearly elucidated, hindering its wide application for therapeutic purposes. The purpose of this investigation was to develop a model of rat sub-acute hepatotoxicity induced by PZA and to explore the affected metabolic pathways by a H NMR-based metabolomics approach complemented with histopathological analysis and clinical chemistry. Rats of both genders were administered with PZA by gavage at doses of 1.0 and 2.0 g kg for 4 weeks. PZA decreased the weights of dosed rats and induced liver injury dose-dependently. The female rats were more sensitive to PZA induced damage. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of the rat liver and serum revealed that PZA produced a status of oxidative stress and disturbances in purine metabolism, energy metabolism and NAD metabolism in a gender-specific and dose-dependent manner. These findings could be helpful to clarify the mechanism of PZA-induced hepatotoxicity and hyperuricemia. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organisms, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

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Section: Animals and Drug Administrationmentioning

confidence: 92%

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach

Zhao

et al. 2017

Toxicol. Res.

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“…Control rats were given the same volume of the dose vehicle alone. The doses selected in this study were referenced to the literature (Kovalenko et al ., ; Shayakhmetova et al ., ). The low, second and third doses exceeded the human dose by 2‐, 4‐ and 8‐fold, respectively.…”

Section: Methodsmentioning

confidence: 99%

Gene expression profiling reveals potential key pathways involved in pyrazinamide‐mediated hepatotoxicity in Wistar rats

Zhang

Jiang

et al. 2012

J of Applied Toxicology

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Pyrazinamide (PZA) is an important sterilizing prodrug that shortens the duration of tuberculosis therapy. However, hepatotoxicity has been reported during clinical trials investigating PZA. To determine the hepatotoxic effects of PZA in vivo and to further investigate the underlying cellular mechanism, we profiled the gene expression patterns of PZA-treated rat livers by microarray analysis. Wistar rats of both sexes were orally administered PZA at doses of 0.5, 1.0 and 2.0 g kg(-1) for 28 days. Body weight, absolute and relative liver weight, biochemical analysis, histopathology, oxidative stress parameters in liver homogenates and changes in global transcriptomic expression were evaluated to study the hepatotoxic effects of PZA. Our results confirm the dose-dependent and sex-related hepatotoxicity of PZA. Female rats were more sensitive to PZA-induced hepatotoxicity than males. Furthermore, changes in the activity of major antioxidant enzymes and nonenzymatic antioxidants (superoxide dismutase, total antioxidant capacity, glutathione and malondialdehyde), indicating the development of oxidative stress, were more significant in the PZA-treated group. PZA-induced gene expression changes were related to pathways involved in drug metabolism, peroxisome proliferator-activated receptor (PPAR) signaling, oxidative stress and apoptosis. Real-time polymerase chain reaction confirmed the regulation of selected genes involved in PZA-hepatotoxicity (Ephx1, Cyp2b1, Gstm1, Gstp1, Fabp7, Acaa1, Cpt-1b, Cyp8b1, Hmox1 and Ntrk1). We observed for the first time that these genes have effects on PZA-induced hepatotoxicity. In addition, drug metabolism and PPAR signaling pathways may play an important role in PZA hepatotoxicity. Taken together, these findings will be useful for future PZA hepatotoxicity studies.

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“…Rats ( n = 6 per group) were divided into four groups that were administered PZA in a 0.5% carboxymethylcellulose (CMC‐Na) solution by gavage at 0 (vehicle control), 0.5, 1.0 and 2.0 g kg –1 day –1 for 28 days. Doses selected in this study were referenced to the previous literature (Kovalenko et al , ; Shayakhmetova et al , ). First, second and third doses exceeded the human dose by 2‐, 4‐ and 8‐fold, respectively.…”

Section: Methodsmentioning

confidence: 99%

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

Zhang

Guo

Hassan

et al. 2016

J of Applied Toxicology

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Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator-activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down-regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co-treatment that acts as a PPARα agonist. In contrast, short-termstarvation significantly aggravated the severity of PZA-induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA-induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA-induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.

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Pyrazinamide and disulfiram effects on male rat's reproductive function

Cited by 3 publications

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Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach

Gene expression profiling reveals potential key pathways involved in pyrazinamide‐mediated hepatotoxicity in Wistar rats

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

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Pyrazinamide and disulfiram effects on male rat's reproductive function

Cited by 3 publications

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Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a1H NMR based metabolomics approach

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a1H NMR based metabolomics approach

Gene expression profiling reveals potential key pathways involved in pyrazinamide‐mediated hepatotoxicity in Wistar rats

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

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Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach

Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a¹H NMR based metabolomics approach