Altered hepatic calcium homeostasis in guinea pigs with halothane-induced hepatotoxicity.
Exposure of guinea pigs to 1% halothane in air for 4 hr resulted in extensive centrizonal hepatic necrosis in 70% of animals examined 2 to 3 days later. In contrast, confluent hepatic necrotic lesions were not present in animals studied 24 hr after halothane exposure; only microvascular fatty change of hepatocytes with occasional necrotic cells was observed at that time (in 84% of animals). This delayed onset of lesion development afforded the opportunity to study microsomal membrane composition and indices of Ca++ homeostasis before and after the onset of halothane-induced hepatic necrosis. Hepatic microsomal cytochrome P-450 levels were unaltered 24 hr after halothane exposure, but fell to approximately 50% of control values at 72 hr. This indicates that such changes were most likely the result of hepatocellular necrosis. Microsomal lipid composition, including the relative proportions of individual phospholipids, was unaltered during halothane-induced hepatotoxicity. In contrast, microsomal Ca++ sequestration, as assessed by 45Ca uptake, was reduced 24 hr after halothane exposure compared with controls (2.76 +/- 1.32 nmol/mg of protein per min, vs. 6.63 +/- 2.88 nmol/mg of protein per min, P less than .001). This early change in microsomal Ca++ uptake was associated with a 10-fold increase in total hepatic Ca++ content at 24 hr. Subsequent changes in hepatic Ca++ content were proportionate to the severity of liver necrosis. The observation that abnormalities of hepatic Ca++ homeostasis antedate the presence of liver cell necrosis is consistent with a role for altered Ca++ fluxes in the mechanism of halothane-induced liver injury.
Farrell
G C
GC
Department of Medicine, University of Sydney, NSW, Australia.
Mahoney
J
J
Bilous
M
M
Frost
L
L
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000493:pharmacokinetics / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006221:Halothane / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008833:Microcirculation; D008862:Microsomes, Liver / Q000378:metabolism; D009336:Necrosis
D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D002118:Calcium; D006221:Halothane