Toxicity of a sevoflurane degradation product incubated with rat liver andrenal cortical slices

Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-l-propene) is a degradati on product of the anesthetic sevoflurane which is created in closed-circuit anesthetic machines. Past in vivo and in vitro studies have implied that C ompound A is nephrotoxic via bioactivation through the cysteine conjugate P -lyase pathway. Although glutathione (GSH) conjugates of Compound A have be en reported, it is not clear if they are formed enzymatically or via direct reaction with GSH. To determine if these metabolites are produced and toxi c, a tissue slice system that first exposes mate Fischer 344 rat liver slic es to volatilized Compound A followed by exposure of rat kidney slices to t he liver incubate was employed. Liver slices exposed to volatilized Compoun d A (6-12 muM medium conc.; similar to 23 ppm) exhibited a loss of K+ by 6 h, which was not seen in kidney slices exposed to Compound A. Aminobenzotri azole, a cytochrome P 450 suicide inhibitor, initially inhibits the cytotox icity of Compound A to liver slices (at these times and concentrations). Th e sequential liver/kidney slice experiments using Compound A have not demon strated nephrotoxic results. GSH conjugates were synthesized and was found to be nephrotoxic at concentrations above 91 muM (18 h), with higher concen trations showing toxicityat earlier times. Additionally, non-enzymatic reac tions Or Compound A with GSH or sulfhydryl-containing medium produces nephr otoxic products. These studies show that Compound A is directly toxic to th e liver, possibly via P 450 activation, and Compound A can react With sulfh ydryls directly to produce a nephrotoxic.