The overall long-term objective of the proposed research is to enhance the clinical safety and efficacy of currently used fluorinated volatile anesthetics, to improve the development of future anesthetics, and to develop in vitro nephrotoxicity models which translate directly to clinical application. The immediate goals are to elucidate mechanisms of anesthetic nephrotoxicity, assess human risk, prevent clinical toxicity, and modernize in vitro screening methods for new anesthetic development. Two issues which drive this research are: 1) Certain fluorinated anesthetics cause nephrotoxicity, which is intrinsically linked to their metabolism by cytochrome P450. Nevertheless, the historically accepted explanation that hepatic P450-catalyzed anesthetic defluorination and systemic fluorosis causes renal insufficiency is now clearly invalid and unapplicable to modern anesthetics, and 2) Sevoflurane, the most recently approved anesthetic, undergoes chemical degradation in clinical anesthesia machines and exposes patients to fluoromethyl-2,2- difluoro-1-(trifluoromethyl)vinyl ether. This fluoroalkene causes profound proximal renal tubular necrosis in rats. In humans, some evidence suggests dose-related clinically significant sevoflurane fluoroalkene nephrotoxicity, however data are very contradictory and the controversy remains unresolved. The potential risk to humans remains ambiguous, in part because the biochemical mechanism of fluoroalkene toxicity in rats and its relevance to humans is unknown. The central hypothesis to he tested in this investigation is that intrarenal metabolism is the critical etiologic factor responsible for the organ-specific nephrotoxicity of certain fluorinated anesthetics and the tubular necrosis caused by fluoroalkene anesthetic degradation products, and that species and drug specific differences in intrarenal anesthetic metabolism confers similar differences in nephrotoxicity. This hypothesis will be tested using complementary in vivo and in vitro approaches in both animal models and humans. Rat studies will evaluate anesthetic metabolism and toxicity using subcellular fractions, isolated proximal tubular segments, and whole animal models. Human studies will evaluate hepatic and renal metabolism in vitro, cultured human kidney cells, and clinical investigations in surgical patients. If intrarenal, rather than hepatic bioactivation underlies anesthetic nephrotoxicity, then screening mechanisms to identify such anesthetics and prevent their toxicity can be revised and future anesthetics more rationally developed. Identifying intrarenal pathways responsible for fluoroalkene breakdown product nephrotoxicity and their interspecies differences will permit adequate assessment of human anesthetic risks. More broadly, resulting biochemical and clinical insights will be applicable to the numerous other nephrotoxic haloalkenes that are ubiquitous environmental contaminants.
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