Fatty Acid Lessens Halothane??s Inhibition of Energy Metabolism in Isolated Hepatocytes

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Abstract
This study has examined whether adverse halothane effects on liver-cell energy metabolism are influenced by the availability of alternate substrates for energy-generating reactions. Halogenated volatile anesthetics affect both energy supply and energy demand in tissues, and cellular energy deficits have been implicated in anesthetic hepatotoxicity. Using hepatocytes isolated from fed rats either pretreated with phenobarbital or not treated (+PB or -PB cells, respectively), we studied the cellular energetic effects of providing fatty acid (oleic acid) along with glucose as substrate(s) for energy metabolism, while exposing the cells to 0%-2% halothane. In -Pb cells incubated with glucose alone, there were halothane dose-related decreases in the oxygen (O2) consumption rate (VO2) land in the balance between adenosine triphosphate (ATP) supply and demand (ATP/ADP ratio), but no effect on lactate metabolism (lactate consumption or production) over the 10-min incubation period. Adding oleate along with glucose (a) raised VO2 but lowered ATP/ADP in the absence of halothane; (b) eliminated the decreases in VO2 and ATP/ADP seen when halothane was introduced; and (c) increased lactate consumption in both the presence and absence of halothane. In + PB cells, VO2 was higher, ATP/ADP lower, and lactate consumption also lower than in -PB cells under comparable conditions. Halothane or oleate effects, or both, on energy metabolism were thus qualitatively similar in +PB and -PB cells incubated without oleate, lactate formation developed as halothane was increased from 0% to 2%, reflecting activation of glycolysis due to insufficient mitochondrial ATP production. Our work with isolated hepatocytes thus suggests that glucose-supported aerobic energy metabolism was only modestly inhibited by halothane at 0% to 2%, in contrast to previous results using isolated perfused liver and a single, higher halothane concentration. We also found that oleate had mixed effects on hepatocellular energy status when provided along with glucose: halothane''s inhibitory effect on ATP supply was reversed, as reported by others; but oleate also increased ATP demand through other, unidentified action(s) not involving halothane. Fatty acids are always available to liver cells in vivo, although at somewhat lower concentrations in fed animals than were used in these in vitro incubations. The general conclusion supported by this study is that by means of any direct action on liver cells, halothane does not interefere with energy metabolism at typical in vivo levels of substrates, O2, and halothane, +PB cells function at higher rates of energy demand and at lower ATP/ADP than do -PB cells and thus more susceptible to development of energy deficits.