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Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska.
Abstract
The role of hepatic energy deficits in the pathogenesis of anesthetic hepatotoxicity is suggested by the involvement of hypoxia in various animal models and by the ability of anesthetics to inhibit mitochondrial oxidations. We have been studying anesthetic effects on hepatocellular energy metabolism using suspensions of intact hepatocytes freshly isolated from phenobarbital-treated or untreated rats (+PB or PB cells, respectively), an experimental system that is metabolically complete yet also biochemically homogeneous and accessible. In the present work, diazepam, lidocaine, thiopental, and enflurane, as well as the combination of thiopental and enflurane, were studied at concentrations similar to those achieved in vivo. Thiopental increased cellular oxygen consumption rate (VO2) in both +PB and - PB cells significantly, as did aminopyrine, a test substrate for PB-inducible cytochrome P450 activity. Diazepam increased VO2 only in +PB cells, as did enflurane, whereas lidocaine did not increase VO2 in either +PB or -PB cells. The combination of thiopental and enflurane significantly decreased VO2 in -PB cells but increased it in + PB cells. The higher VO2 in +PB cells compared to -PB cells, seen with all drugs tested (except lidocaine), was eliminated by prior addition of the P450 inhibitor metyra-pone.
Starting from steady states of oxygen metabolism, with VO7 offset by O2 supply from an overlying gas phase and PO2 stabilized at 24 mm Hg, aminopyrine significantly lowered extracellular PO2, increased lactate production, and decreased high energy phosphate levels within 10 minutes. These changes in energy status were limited to +PB cells and were largely prevented by running incubations at higher PO2 levels (>20 mm Hg throughout), suggesting that hypoxia due to P450-mediated VO2increased had been mainly responsible. On the other hand, in contrast to either drug alone, the combination of thiopental and enflurane produced statistically significant hepatocellular energy impairment that was seen even in -PB cells; this impairment could not be reversed at higher Pu2, a finding that is consistent with direct inhibition of the mitochondrial respiratory chain. These results support the possibility that with increases in oxygen demand (P450 induction), decreases in oxygen supply (hypoxia), and/or other agents present with interacting effects on oxygen-supported metabolism, drugs and doses that are considered safe during anesthesia might nonetheless promote hepatocellular energy deficits as a result of hypoxic or nonhypoxic mechanisms.
Key Words: ANESTHETICS, VOLATILE—enflurane. • ANESTHETICS, INTRAVENOUS—thiopental. • ANESTHETICS, LOCAL—lidocaine. • COMPLICATIONS—hepatotoxicity. • HYPNOTICS, BENZODIAZEPINESdiazepam. LIVER—hepatotoxicity.
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