ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg116
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Department of Pharmacology and Pharmacotherapy, University of Pécs, Medical School
* To whom correspondence should be addressed. E-mail: zoltan.gregus{at}aok.pte.hu.
Reduction of the pentavalent arsenate (AsV) to the thiol-reactive arsenite (AsIII) toxifies this environmentally prevalent form of arsenic, yet its biochemical mechanism in mammals is incompletely understood. Purine nucleoside phosphorylase (PNP) has been shown recently to function as an AsV reductase in vitro, provided its substrate (inosine or guanosine) and an appropriate dithiol (e.g., dithiothreitol, DTT) were present. It was of interest to know if this ubiquitous enzyme played a significant role in reduction of AsV to AsIII in vivo. Two approaches were used to test this. First, it was examined if compounds, which influenced AsV reduction by purified PNP (i.e., nucleosides, thiols, and PNP inhibitors), would similarly affect reduction of AsV by human erythrocytes. Erythrocytes were incubated with AsV, and the formed AsIII was quantified by HPLC-hydride generation-atomic fluorescence spectrometry. The red blood cells reduced AsV at a considerable rate, which could be enhanced by inosine or inosine plus DTT. These stimulated AsIII formation rates were PNP-dependent, as PNP inhibitors strongly inhibited them. In contrast, PNP inhibitors had little if any inhibitory effect on AsIII formation in the absence of exogenous inosine, indicating that this basal rate of AsV reduction is PNP-independent. Second, the role of PNP in reduction of AsV in vivo was assessed also by investigating the effect of the PNP inhibitor BCX-1777 on the biotransformation of AsV in control and DTT-treated rats with cannulated bile duct and ligated renal pedicles. Although it abolished hepatic PNP activity, BCX-1777 influenced neither the biliary excretion of AsIII and monomethylarsonous acid, nor the tissue concentration of AsV and its metabolites in either group of AsV-injected rats. Thus, despite its in vitro activity, PNP does not appear to play significant role in AsV reduction in human erythrocytes and in rats in vivo. Further research should clarify the in vivo relevant mechanisms of AsV reduction in mammals.
© 2003 Society of Toxicology
Biotransformation and Toxicokinetics
Arsenate Reduction in Human Erythrocytes and Rats - Testing the Role of Purine Nucleoside Phosphorylase
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