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Peroxynitrite Delivery Methods for Toxicity Studies

Peroxynitrite Delivery Methods for Toxicity Studies. Wang, Chen; Deen, William M. (Department of Chemical Engineering and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139, USA). Chemical Research in Toxicology, 17(1), 32-44 (English) 2004 American Chemical Society. CODEN: CRTOEC. ISSN: 0893-228X. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) The endogenous synthesis of peroxynitrite (ONOO-) has been implicated in a no. of diseases, but assessments of its cytotoxicity and genotoxicity have been hampered by its extremely short half-life under physiol. conditions (<20 ms) and the consequent difficulty in exposing cells to known concns. of it over at least several hours. Two methods for peroxynitrite delivery to cell cultures were investigated, one involving steady infusion of preformed ONOO- and the other based on the continuous in situ synthesis of ONOO- from NO and O2-. In the latter, NO was supplied by diffusion through gas permeable tubing and O2- was generated using the hypoxanthine-xanthine oxidase reaction. The performance of both methods was assessed by measuring the rates of formation of tyrosine derivs. (dityrosine and nitrotyrosine) that are commonly employed as biomarkers for peroxynitrite. Exptl. results in the absence of cells were compared in each case with predictions from kinetic models. In the infusion system, the measured dityrosine and nitrotyrosine yields were in excellent agreement with those predicted from the model. To characterize the other system, expts. were performed first to det. the kinetics of hypoxanthine oxidn. by xanthine oxidase and uric acid oxidn. by uricase. Simulations of the complex reaction network in the complete synthesis system suggested that dityrosine should be the major product there, that the yields of both tyrosine derivs. should be very sensitive to the relative rates of NO and O2- delivery, and that equal rates for NO and O2- should maximize those yields. Expts. performed under the predicted optimal conditions showed much lower levels of dityrosine than expected and no detectable nitrotyrosine. 10102-43-9 and 68-94-0 are just another two chemicals used in this study. The unexpectedly low yields of tyrosine products could be explained largely by the partial inactivation of both xanthine oxidase and uricase by peroxynitrite-derived NO2 and CO3- radicals. We conclude that continuous infusion of peroxynitrite is the more promising approach. .