Elsevier

Transplantation Proceedings

Volume 42, Issue 9, November 2010, Pages 3820-3822
Transplantation Proceedings

Experimental study
Other model
Oxidant and Antioxidant Activity in Rabbit Livers Treated With Zoledronic Acid

https://doi.org/10.1016/j.transproceed.2010.06.017Get rights and content

Abstract

Zoledronic acid (ZA), a nitrogen-bearing bisphosphonate, is used to treat the hypercalcemia associated with cancer. In addition to its antiumor effects, it acts as an osteoclast inhibitor. To investigate the effects of ZA on oxidative stress and antioxidants, we studied reduced glutathione (GSH) and antioxidant gamma glutamate cysteine, including nitrite and nitrate, which are endproducts of nitric oxide (NO) as well as malondialdehyde (MDA) in rabbit liver tissue. In the study ZA (100 μg/kg) was administered to 7 rabbits that were fed ad libitum for comparison with untreated controls. MDA was studied using Thiobarbituric acid–reactive substance reduction, NO using cadmium reduction, GSH using an enzymatic method yielding dithinitrobenzene yellow substance. We observed significantly higher MDA and NO levels in the ZA group (P < .0001), whereas GSH levels were significantly lower (P < .0001). Tissues were examined histopathologically. According to our results we find ZA induced rabbit liver oxidative stress and decreases with antioxidant levels in liver tissue. Further studies are needed to explore the safe use of this agent.

Section snippets

Material and Methods

The chemical structure of ZA (Sigma Cas. No. 118072-93-8) is designated as (1-hydroxyl-2-imidazole-1-yl-phosphonoethyl) phosphonic acid monohydrate; its chemical formula is C5H10N2O7P2 · H2O with molecular weight of 290.1 g/mol (Fig 1). ZA is available as a white crystalline powder that is reconstituted for injection with 5 mL of sterile water (USP) to be diluted in 100 mL of 0.9% sodium chloride (USP) or of 5% dextrose (USP) for intravenous (IV) injection. Animal investigations were performed

Results

We observed that GSH levels were significantly decreased in the ZA (1.7 ± 0.3) compared with the control group (2.5 ± 0.2). NO and MDA levels were significantly increased in the ZA group (24.4 ± 2.5 and 99.9 ± 28; both P < .0001) compared with controls (11.9 ± 1.5 and 43.5 ± 5.5; respectively; Table 1). The histopathological changes between the groups were not significantly different.

Discussion

ZA is a third-generation nitrogen-containing parenteral bisphosphonate indicated for the treatment of bone metastases due to solid tumors or multiple myeloma, for the hypercalcemia of malignancy, and for prevention of posttransplant bone fractures.10, 15 Their selective action on osteoclasts is due to effective endocytosis of bisphosphonates. The metabolites inhibit bone resorption by inducing osteoclast apoptosis, likely due to inhibition of ATP-dependent enzymes.16 The inhibition of

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