Cisplatin nephrotoxicity: Inhibition of γ-glutamyl transpeptidase blocks the nephrotoxicity of cisplatin without reducing platinum concentrations in the kidney☆,☆☆,★,★★
Section snippets
Experimental protocol
The treatment protocol has been previously described in detail.3 Briefly, male Sprague-Dawley rats (275 to 300 gm) were lightly anesthetized with methoxyflurane (Metofane, Pitman-Moore, Mundelein, Ill.). A 24-gauge Teflon polytetrafluoroethylene 0.75-inch catheter (Critikon, Tampa, Fla.) was placed in the tail vein. Catheters were capped with intermittent injection caps (Critikon) and flushed with 0.2 ml heparinized saline solution. All solutions were injected through the catheter. The animals
RESULTS
Urine was collected from rats for 3 hours after intravenous injection of 6 mg/kg cisplatin. Platinum concentrations in the urine of acivicin pretreated and control animals is shown in Table I. Animals were injected with an average of 1.8 mg of cisplatin. The animals excreted approximately 30% of the platinum during the first 3 hours. Pretreatment with acivicin to inhibit GGT activity did not affect the amount of platinum excreted. Analysis of the data with a t test showed p > 0.5, which
COMMENT
The mechanism by which cisplatin kills nondividing cells is unclear. Inhibitors of this toxicity may provide insight into this pathway. We analyzed the amount of platinum excreted in the urine during the 3 hours after treatment with cisplatin. Approximately 30% of the platinum was excreted in rats injected with a nephrotoxic dose of cisplatin. Pretreatment of the animals with acivicin to inhibit GGT activity did not change the amount of platinum excreted. These data suggest that inhibition of
Acknowledgements
We thank Mr. James Nicholson from the Trace Metals Laboratory at the University of Virginia and Ms. Mary Katherine Large for their assistance with these studies.
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Cited by (24)
Cisplatin chemotherapy and renal function
2021, Advances in Cancer ResearchCitation Excerpt :However, proximal tubular cells are not replicating, suggesting an alternative mechanism of toxicity (Tanase et al., 2019). The cellular process of nephrotoxicity can be attributed to local accumulation of cisplatin inside the renal proximal tubule by membrane transportation, and intracellular conversion of the drug into toxic metabolites (Hakiminia et al., 2019; Hanigan, Gallagher, & Taylor, 1996). Among the reported mechanisms of cisplatin nephrotoxicity are dysregulation of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, inflammatory responses (macrophage/monocyte infiltration into renal cortex and medulla), apoptosis, necrosis and autophagy (Hanigan & Devarajan, 2003).
Accumulation of BNP7787 in human renal proximal tubule cells
2011, Journal of Pharmaceutical SciencesCitation Excerpt :In animal studies, Ormstad and Uehara14 noted that transmembranal uptake of dimesna (BNP7787) is expected to require energy and involve an active transport mechanism; they demonstrated the uptake of BNP7787 in rat kidney perfusions and rat kidney cells. Additionally, in vitro, we have observed that BNP7787 and BNP7787-derived mesna–disulfide heteroconjugates can inhibit human γ-glutamyltranspeptidase (GGT) and aminopeptidase N (APN) enzymes15,16 that are postulated to be important in converting cisplatin to a nephrotoxigenic species.22–29 If there is metabolism and local action and/or local uptake of BNP7787 by renal tubular cells, it is likely that a protective mechanism exists, whereby BNP7787's disulfide bond is reduced to yield BNP7787-derived mesna, the reactive thiol (Fig. 1).
Metabolism of cisplatin to a nephrotoxin
2009, ToxicologyRole of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity
2009, Biomedicine and PharmacotherapyCitation Excerpt :There was no correlation between platinum concentrations in the kidney and cisplatin-induced nephrotoxicity indicating that differential uptake of platinum into the kidney did not affect renal toxicity in this study. These data are consistent with earlier findings that inhibition of GGT or cysteine S-conjugate beta-lyase (enzymes in the metabolism of cisplatin to a nephrotoxin) blocked the nephrotoxicity of cisplatin but did not alter the level of platinum in the kidney [8,10,28]. This lack of correlation may reflect the small percentage of the total cisplatin dose that is bioactivated and responsible for the renal toxicity [27].
Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies
2008, Kidney InternationalExpression of γ-glutamyltransferase in cancer cells and its significance in drug resistance
2006, Biochemical Pharmacology
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From the Departments of Cell Biologyaand Obstetrics and Gynecology,bUniversity of Virginia.
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Supported by grant No. R01-CA57530 from the National Cancer Institute, National Institutes of Health.
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Reprint requests: Marie H. Hanigan, PhD, Box 439, School of Medicine, University of Virginia, Charlottesville, VA 22908.
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0002-9378/96 $5.00 + 0 6/6/74487