Effect of methotrexate (MTX) on NAD(P)+ dehydrogenases of HeLa cells: malic enzyme, 2-oxoglutarate and isocitrate dehydrogenases

Caetano, N.N; Campello, Annibal P.; Carnieri, Eva Gunilla Skare; Klüppel, Ma. Lúcia W.; Oliveira, Maria Benigna Martinelli de

doi:10.1002/(sici)1099-0844(199712)15:4<259::aid-cbf749>3.0.co;2-d

Cited by 43 publications

(20 citation statements)

References 22 publications

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“…It has been demonstrated that the cytosolic NAD(P)-dependent dehydrogenases (Vogel et al, 1963;Babiak et al, 1998) and NADP malic enzyme are inhibited by MTX, indicating that the drug could decrease the availability of NADPH in cells by inhibiting pentose cycle enzymes (Caetano et al, 1997). Due to the interference with the pentose phosphate shunt, MTX may also depress nucleic acid metabolism.…”

Section: Introductionmentioning

confidence: 99%

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

et al. 2006

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Methotrexate (MTX), a folic acid antagonist widely used for the treatment of a variety of tumors and inflammatory diseases, affects normal tissues that have a high rate of proliferation, including the hematopoietic cells of the bone marrow and the gastrointestinal mucosal cells. To elucidate the role of free radicals and leukocytes in MTX-induced oxidative organ damage and the putative protective effect of L-carnitine (L-Car), Wistar albino rats were administered a single dose of MTX (20 mg/kg) followed by either saline or L-Car (500 mg/kg) for 5 days. After decapitation of the rats, trunk blood was obtained, and the ileum, liver, and kidney were removed for histological examination and for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content. Our results showed that MTX administration increased the MDA and MPO activities and collagen content and decreased GSH levels in all tissues, while these alterations were reversed in L-Car-treated group. The elevated serum TNF-alpha level observed following MTX treatment was depressed with L-Car. The oxidative burst of neutrophils stimulated by Annexin V was reduced in the saline-treated MTX group, while L-Car abolished this inhibition. Similarly, flow cytometric measurements revealed that leukocyte apoptosis was increased in MTX-treated animals, while L-Car reversed these effects. Severe degeneration of the intestinal mucosa, liver parenchyma, and glomerular and tubular epithelium observed in the saline-treated MTX group was improved by L-Car treatment. These results suggest that L-Car, possibly via its free radical scavenging and antioxidant properties, ameliorates MTX-induced oxidative organ injury and inhibits leukocyte apoptosis. Thus, supplementation with L-Carnitine as an adjuvant therapy may be promising in alleviating the systemic side-effects of chemotherapeutics.

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Section: Introductionmentioning

confidence: 99%

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

et al. 2006

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“…8 The eect of MTX on several aspects of energy metabolism, in mitochondria and tumour cells, has been extensively investigated by several authors. 9±14 It is noteworthy that 2-oxoglutarate, pyruvate, isocitrate and malate dehydrogenases, 12,15,16 all NAD -dependent enzymes obtained from rat liver or HeLa cell mitochondria, are inhibited by MTX. Additionally, cytosolic NAD(P)-dependent dehydrogesases 17,18 are also inhibited by MTX.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it was demonstrated that the NADP malic enzyme of HeLa cells is inhibited by MTX, suggesting that the drug could decrease the availability of NADPH in cells. 16 Malic enzyme and the pentose cycle are the main sources of NADPH in proliferating cells. 19 In addition, NADPH is used by glutathione reductase to maintain the reduced state of cell glutathione, which is known as an important protective agent against reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the evidences for a relationship between glutathione and MTX eects 6 besides the known function of this tripeptide in protection against ROS, the relation between the pentose cycle and the maintenance of an intracellular pool of GSH, 20 the inhibition of several dehydrogenases by MTX, 12,15,16 and the use of LCV in recuperation of the eect of MTX, 5 the purpose of our investigation is to evaluate the actions of MTX on pentose cycle enzymes and the activity of the enzymes involved in the mechanisms of enzymic defence against ROS, in HeLa cells. The eect of MTX is also investigated on cellular levels of total glutathione.…”

Section: Introductionmentioning

confidence: 99%

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Methotrexate: pentose cycle and oxidative stress

Babiak

Campello

Carnieri

et al. 1998

Cell Biochem. Funct.

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141

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The effect of methotrexate (MTX) and leucovorin (LCV) on pentose cycle enzymes and the activity of enzymes involved in enzyme defence mechanisms against ROS in HeLa cells, were studied. The effect of MTX was also investigated on the cellular levels of glutathione. MTX inhibited the activity of glucose-6-phosphate and 6-phosphogluconate dehydrogenases. The activities of glutathione reductase and gamma-glutamylcysteine synthetase were also inhibited by the drug. No effect was observed on the activities of catalase, superoxide dismutase or transketolase. LCV had no effect on any of the enzymes studied. MTX decreased the cellular levels of glutathione (70 per cent), while the presence of LCV and glutamine did not interfere with the effect of MTX. The net results appear to show that the biological situation resulting from treatment with MTX leads to a reduction of effectiveness of the antioxidant enzyme defence system.

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“…MTX treatment increases biomarkers associated with liver injury and are involving in hepatotoxicity [6]. MTX inhibits enzymes corresponding in production of the main sources of nicotine amide adenine dinucleotide (NADPH) resulting in intracellular decreases of NADPH [7]. Following NADPH decreasing, glutathione decreases and hepatocytes become vulnerable against reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

The use of 99mTc-phytate for assessment the protective effect of vitamin E against hepatotoxicity induced by methotrexat in rat

et al. 2018

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Hepatotoxicity is one of the most common side effects of methotrexate (MTX) therapy in patients. The aim of this study was to evaluate the protective effect of vitamin E against MTX-induced hepatotoxicity using 99m Tc-phytate as a radiopharmaceutical agent in animals. Rats were divided into five groups as follows: control, solvent, Vit E (100 mg/kg), MTX (20 mg/kg) and Vit E + MTX. Animals were intraperitoneally injected with Vit E for 17 days before MTX injection and continued for 4 days. Tc-phytate was injected into the tail of rats after the 21 days of Vit E administration. Percentage of the injected dose per gram of liver and spleen tissues (%ID/g) was calculated in treated rats. Liver imaging was obtained with gamma camera. In other experiment, liver of treated rats was assessed for histopathology. Tc-phytate uptake (%ID/g) of livers in control, solvent, Vit E, MTX and Vit E + MTX groups were 8.99% ± 1.37, 8.53% ± 2.91, 8.65% ± 3.84, 3.22% ± 1.09 and 8.38% ± 2.68. Vit E administration resulted in a significant increase of the level of %ID/g in MTX-injected animal. Vit E pre-treatment improved the shape of liver in MTX-treated rat which was seen abnormal view in planar imaging. Histophatological examinations approved the protective effect of Vit E against MTX-induced hepatotoxicity in rats. The results of this study show that Vit E significantly attenuates the MTX-induced hepatotoxicity in rats, and 99m Tc-phytate is an acceptable radiopharmaceutical agent for assessment of liver and spleen damages in the animal model.

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Effect of methotrexate (MTX) on NAD(P)+ dehydrogenases of HeLa cells: malic enzyme, 2-oxoglutarate and isocitrate dehydrogenases

Cited by 43 publications

References 22 publications

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

Methotrexate: pentose cycle and oxidative stress

The use of 99mTc-phytate for assessment the protective effect of vitamin E against hepatotoxicity induced by methotrexat in rat

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