1. Modulation of the metabolism of cis-platin in blood plasma by glutathione.
- Author
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Sooriyaarachchi, Melani, Gibson, Matthew A., Lima, Bruno dos S., and Gailer, Jürgen
- Subjects
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BLOOD plasma substitutes , *GLUTATHIONE , *ANTINEOPLASTIC agents , *NEPHROTOXICOLOGY , *OTOTOXICITY - Abstract
The anticancer drug cis-platin (CP) is in worldwide clinical use to treat a variety of cancers, but is inherently associated with severe toxic side effects. Previous animal studies revealed that its neurotoxicity can be significantly reduced by the coadministration of l-glutathione (GSH) without affecting the anticancer effect. The underlying molecular mechanism, however, has remained elusive. Since the bloodstream is a likely biological compartment where CP-derived hydrolysis products may react with GSH, we have employed a recently developed metallomics tool to gain insight into the interaction of CP and GSH in rabbit plasma in vitro. After the addition of increasing GSH/CP molar ratios to plasma (25:1, 50:1, and 100:1), the determination of the Pt distribution 5 min and 2 h later revealed the formation of a Pt-GSH complex that did not bind to plasma proteins. The simultaneously obtained Zn distribution in plasma revealed a progressively more pronounced perturbation of the Zn metalloproteome with increasing GSH/CP molar ratios at the 5 min time point, which partially reversed at the 2 h time point. The formation of Pt-GSH species in plasma is therefore likely to be directly involved in the process by which GSH protects mammalian organisms from CP-induced neurotoxicity, nephrotoxicity, and possibly other organ-based toxicities. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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