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Effects of a preliminary 50 mg/kg dose of cyclophosphamide (CP) on pulmonary hydroxyproline accumulation due to 250 mg/kg cyclophosphamide. Mice were given either saline or a single dose of 50 mg/kg cyclophosphamide on day-7, followed by a single dose of 250 mg/kg cyclophosphamide on day 0. Controls received an injection of saline or 50 mg/kg cyclophosphamide on day-7. followed by saline on day 0. Hydroxyprolinc content was measured on day 28. Data are expressed as means ±SE. n = 7-10 for all time points. *. significantly different from saline/saline (/>< 0.05).
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A single i.p. dose of cyclophosphamide produces lung cell injury and fibrosis in mice. Although cyclophosphamide is activated by the cytochrome P-450 mixed function oxidase (MFO) system, a role for this system in the development of lung injury has not been established. The involvement of other metabolic pathways, such as cooxidation via prostagland...
Context in source publication
Context 1
... with inhibitors alone had no significant effects on lung hydrox yproline content, compared to saline (data not shown). A 50 mg/kg dose of cyclophosphamide did not protect against the development of lung fibrosis due to a 250 mg/kg dose given 7 days later (Fig. 6). A single dose of 50 mg/kg cyclophospha mide followed by saline produced no greater accumulation of hydroxyproline than did two doses of ...
Citations
... In the present study, the electrophoretic calcium moieties of (Fig. 3b). This might be attributed to efficiency of the paracetamol in conversion of an active hydrogen atom from these biologically active macromolecules [103]. This leads to variations in number and arrangement of the bands. ...
Paracetamol is the most commonly used analgesic-antipyretic drugs. Its excess use causes an acute hepatotoxicity. It is well known that the Bacillariophyta alga Amphora coffeaeformis is rich in many photosynthetic pigments with antioxidant activities as well as a series of biologically active substances. The current work has been designed to study the phytochemical composition of different A. coffeaeformis algal extracts to select the most effective one. It was verified that acetone A. coffeaeformis algal extract is rich in various pigments and polyphenolic compounds (β-carotene (9.31 ± 0.06 mg·g-1), gallic acid (28.31 µg·g-1), catechin (38.08 µg·g-1) and p-coumaric acid (38.69 µg·g-1)). The pigments and phenolic profiles in acetone extract were determined in addition to isolation of β-carotene and fucoxanthin which exhibited free radical scavenging activity by 74.80% and 69.40%, respectively. Therefore, the highest total antioxidant capacity and free radical scavenging activity were noticed with this extract. Consequently, efficiency of this algal extract was evaluated against hepatic intoxication induced by paracetamol in rats. The biochemical measurements (liver functions and markers of oxidative stress) were assayed. Moreover, the native protein, lipid and calcium moieties of native protein patterns in addition to catalase (CAT); peroxidases (POX); α- and β-esterase (EST) isoenzymes and genomic DNA patterns were electrophoretically detected in liver tissues. It was found that paracetamol caused significant (P < 0.05) elevation in serum liver functions associated with decline in activities of the antioxidant enzymes in that tissues. Also, it caused alterations represented electrophoretically at qualitative level from variations in the bands number and arrangement. So that, the paracetamol treated group was noticed with the lowest similarity index (SI). In addition, it caused abnormalities at the quantitative level through variations in quantity of normal bands. Algal extract restored all the biochemical functions to normal levels in the algal extract simult-treated and pre-treated groups. Furthermore, it exhibited ameliorative effect against the electrophoretic alterations through restoring the absent normal bands and hiding the abnormal ones and hence increasing the SI values especially in the extract simult-treated group. Algal extract exhibited antagonistic effect against the hepatic injury and the deleterious effects induced by paracetamol in the extract simult-treated group.
... Classical P450 inhibitors such as SKF-525A did not attenuate pulmonary thymidine incorporation, a marker of tissue injury, associated with administration of cyclophosphamide, whereas pretreatment with 1-ABT lowered thymidine incorporation into lung DNA on days 3 and 10, but not on day 7. Agents, such as indomethacin and aspirin, which inhibit arachidonic acid pathways independent of cytochrome P450, similarly reduced levels of thymidine incorporation in the lung. Although differences were found in the protective effects of these agents in liver and lung, it appears that oxidation of cyclophosphamide by the cytochrome P450 system is not essential for the development of pulmonary toxicity associated with cyclophosphamide [221]. Gene therapy to increase expression of CYP2B in tumors provides a strategy for increasing tumor rather than systemic toxicity of cyclophosphamide [222]. ...
1-Aminobenzotriazole (1-ABT) is a pan-specific, mechanism-based inactivator of the xenobiotic metabolizing forms of cytochrome P450 in animals, plants, insects, and microorganisms. It has been widely used to investigate the biological roles of cytochrome P450 enzymes, their participation in the metabolism of both endobiotics and xenobiotics, and their contributions to the metabolism-dependent toxicity of drugs and chemicals. This review is a comprehensive evaluation of the chemistry, discovery, and use of 1-aminobenzotriazole in these contexts from its introduction in 1981 to the present.
... Calcium-binding proteins have a specific role in resistance to the bifunctional alkylating agents which include CYP 88 . In the present study, CYP induced alterations in calcium-binding proteins due to role of this alkylating agent in conversion of an active hydrogen atom from these biologically active macromolecules 89 . The antioxidant enzymes expressed mainly in the liver tissue which is considered as one of the highest antioxidant enzyme capacity in the body due to its major metabolic roles 90 . ...
Drugs used for treatment of cancerous diseases by mean of chemotherapy are often limited due to their severe undesirable side effects in multiple organs. Cyclophosphamide (CYP) belongs to class of the cytotoxic bifunctional alkylating agents. In the current study, it was revealed that CYP caused significant (P˂0.05) elevation in levels of different biochemical measurements. Carob extract exhibited beneficial effect through lowering of all elevated parameters. Furthermore, CYP caused decline in total antioxidant capacity (TAC) level in association with elevation of lipid peroxidation (LPO) level and significantly (P˂0.05) in liver tissue. Carob extract restored TAC and lowered LPO level. CYP caused several histopathological alterations in the hepatocytes and carob extract minimized severity of these alterations. The similarity index percent (SI %) in the native electrophoretic protein, lipoprotein and calcium moiety of protein patterns was represented by lowest values (87.50, 66.67 and 70.59, respectively) with the CYP-treated group. The SI % values increased in all carob treated groups. In all electrophoretic isoenzymes, the SI % value was represented by the lowest value (60.00, 66.67, 66.67 and 53.33 respectively with catalase (CAT), peroxidase (GPx), α- and β-esterase (EST) patterns) in CYP-treated group. While in all carob treated groups, the SI % value reached the highest value (100.00). Furthermore, CYP induced cleavage of the genomic DNA and the carob extract maintained the DNA integrity. The study concluded that carob showed ameliorative effect against alterations induced by CYP at biochemical, histopathological and molecular levels in liver tissue of rats.
... In this context it is interesting that e.g., prostaglandin H synthase (which has recently been found to be expressed in hepatocytes, 51 has been shown to be able to activate CPA. 52 Also, CPA-inactivating enzymes such as aldehyde dehydrogenase may be modulated by PKA-dependent phosphorylation. To simplify the functional analysis of CYP2B1 phosphoprotein in CPA activation, we replaced the phosphoacceptor Ser128 residue by Ala128 or Gly128 or Asp128 within the PKA recognition motif Arg125-Arg126-Phe127-Ser128 to generate 3 variants of CYP2B1 that could (presumably) not undergo phosphorylation, at least not at this site. ...
An important feature of cytochrome P450 (CYP) 2B1 is its high ability to convert the prodrug cyclophosphamide (CPA) to therapeutically cytotoxic metabolites, resulting in interstrand DNA-cross-linking and cell death. We have examined whether and how the phosphorylation of CYP2B1 influences CPA metabolic activation in vitro and in vivo. We found first that only part of the total CYP2B1 pool undergoes phosphorylation. This part is fully inactivated. Second, phosphorylation of CYP2B1 in intact hepatocytes reduced by up to 75% toxification of CPA to mutagenic metabolites (totally dependent on the same preferentially CYP2B-catalyzed 4-hydroxylation of CPA as is the generation of highly cytotoxic species). Third, the phosphoacceptor-serine 128 of CYP2B1 in the consensus sequence for interaction with the protein kinase A represents an on/off switch for the activation of CPA depending on the phosphorylation conditions in the cell. Fourth, evidence is presented that the above-described events also occur in vivo. In conclusion, a successful therapy with CPA, helped by forced expression of CYP2B1 in tumor cells (as recently proposed) will, in addition, be profoundly modified by its phosphorylation status. © 2001 Wiley-Liss, Inc.
La ciclofosfamida (CFM) se ha estudiado como agente quimioterapéutico durante muchos años. Esta investigación tuvo como objetivo estudiar las interacciones cuánticas-químicas in silico del ácido elágico (AEL) y su similitud con el CFM. La teoría del coeficiente de transferencia de electrones se utilizó como base para calcular el equivalente en radios de Bohr (a°). La distancia calculada es el equivalente al salto HOMO-LUMO de un electrón desde la molécula A1 a la molécula A2 si ambas moléculas son de la misma especie y el salto de A1 a B2, si la interacción es de la especie A a una especie B diferente (bandas cruzadas). Se encontró similitud entre las dos sustancias CFM y AEL. Un diagrama de bigotes muestra los coeficientes de transferencia de electrones de las dos sustancias (CTE) en interacciones con los AAs. Estas interacciones presentan dos patrones de oxidación-reducción similares; parecen ser diagramas paramétricos. Los diagramas debajo del pozo cuántico son del CFM y los diagramas de reducción de óxido del AEL están arriba. Por lo tanto, se concluye que el CFM oxida con mayor poder que el AEL, por lo que el AEL es menos agresivo que el CFM.
Background:
Apelin-13 is an endogenous adipocytokine known for its antioxidant, anti-inflammatory, and antiapoptotic properties.
Objective:
We aimed to investigate the possible protective effects of exogenous Apelin-13 administration on oxidative stress, inflammation, and apoptosis induced by the cytotoxic agent cyclophosphamide (CP) in the lungs.
Methods:
Twenty-four male Wistar albino rats were divided into four groups: Control (saline), CP (200 mg/kg), Apelin-13 (10 μg/kg/day), and CP+Apelin-13. CP was administered as a single dose on the fifth day, and apelin-13 was administered intraperitoneally for five days. Total oxidant status (TOS), total antioxidant status (TAS), and lipid peroxidation were determined with spectrophotometry, TNFα and IL1β were determined with ELISA, APJ, Sirt1, NF-kB, and p53 mRNA expressions were determined with qRT-PCR, cytochrome (Cyt) C and caspase-3 protein expressions were studied with western blotting in lung tissues. The oxidative stress index (OSI) was also calculated. Furthermore, serum surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6) levels were measured with ELISA.
Results:
Compared to the control group, TOS, OSI, lipid peroxidation, TNFα, IL1β, cyt C, caspase-3, APJ, NF-kB, and p53 were higher, and Sirt1 was lower in the lung tissue of rats in the CP group. Serum KL-6 and SP-D levels were higher in the CP group. Co-administration of CP with Apelin-13 completely reversed the changes induced by CP administration.
Conclusion:
Exogenous Apelin-13 treatment protected lung tissue against injury by inhibiting cyclophosphamide-induced oxidative stress, inflammation, and apoptosis. This protective effect of apelin-13 was accompanied by upregulation of the Sirt1 and downregulation of NF-kB/p53 in the lungs.
We investigated using immunohistochemistry the possible protective effects of ascorbic acid, α-tocopherol and selenium during chemotherapy treatment with cyclophosphamide. Thirty female Wistar rats were divided into five groups of six: group 1, untreated control; group 2, 75 µg/kg cyclophosphamide; group 3, 75 µg/kg cyclophosphamide + 150 µg/kg/day α-tocopherol; group 4, 75 µg/kg cyclophosphamide + 200 µg/kg/day ascorbic acid and group 5, 75 µg/kg cyclophosphamide + 40 ppm/kg/day selenium. Proliferating cell nuclear antigen (PCNA) staining was used to detect cell proliferation and AT1 was used to evaluate structural damage. Caspase-8, caspase-9 and caspase-3 signal molecules were used to investigate apoptosis. In group 2, epithelium, alveolar macrophages, infiltrated lymphocytes and connective tissue were immunostained moderately to strongly with PCNA. Bronchus, alveolar wall and infiltrated lymphocytes were immunostained moderately to strongly with AT1 and diffuse strong caspase immunoreactions were observed throughout the lung tissue. AT1 and caspase immunoreactions in groups 4 and 5 were similar to group 2. In group 3, PCNA immunoreactivity was strong in the bronchiolus epithelium, endothelial cell nuclei and in stacks of infiltrated lymphocyte cell nuclei. In group 3, AT1 and caspase immunoreactions were identical to group 1. It appears that α-tocopherol inhibits lung tissue damage in rats during chemotherapy.
Objective: To evaluate the protective effect of Zataria multiflora extract, an antioxidative medicinal plant, against cyclophosphamide (CP)-induced oxidative lung damage in mice.
Methods: Mice were intraperitoneally pre-treated with various doses of Zataria multiflora extract (50, 100, 200, and 400 mg/kg) once daily for 7 consecutive days. Animals were then injected with a single 200 mg/kg intraperitoneal dose of CP 1 h after the last administration of O. vulgare. Twenty-four hours later, mice were euthanized, the lungs were immediately removed, and biochemical and histological studies were conducted.
Results: A single dose of CP markedly altered the levels of several biomarkers associated with oxidative stress in lung homogenates. Pretreatment with Zataria multiflora significantly inhibited the elevation of lipid peroxidation level and the depletion in glutathione content, and superoxide dismutase and catalase activities induced by CP in lung. In addition, Zataria multiflora effectively alleviated CP-induced histopathological abnormality and pulmonary damages in mice lung tissues.
Conclusions: The results reveal that Zataria multiflora protects lung tissues from CP-induced toxicity and suggest a role for oxidative stress in the pathogenesis of lung toxicity produced by CP in mice. Because Zataria multiflora has been extensively used as an additive agent and is regarded as safe, it may be used concomitantly as a good supplement for reducing organ toxicity in patients undergoing chemotherapy, besides their consolidated ethnopharmacological uses.
The aim of the present study was to investigate the correlation between ultrastructural changes of the liver and lung, intensity of lipid peroxidation (measured by the level of malondialdehyde (MDA)) in liver and lung tissue homogenates and the alterations in the activities of superoxide dismutase (Cu,Zn-SOD) and glutathione reductase (GSSG-R) following cyclophosphamide (CP) administration. Treatment with CP caused an increase in MDA level in liver and lung tissue homogenates. No statistical differences, however, were noted in GSSG-R and SOD activities in liver and lung homogenates. The paper discusses a potential link between the findings of biochemical analysis and the morphological changes found within the liver and lung, especially the apoptosis-like changes.
