Altered Hepatic Calcium Homeostasis in Guinea Pigs with Halothane-Induced Hepatotoxicity

Farrell, Geoffrey C.; Mahoney, J; Bilous, Michael; Frost, Linda

doi:10.1097/00132586-198906000-00003

Cited by 7 publications

(14 citation statements)

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“…As expected from our earlier study, 9 tion spectrometry, as previously described. 9,26 Liver was ho-there was a threefold increase in total hepatic calcium mogenized in 5% lanthanum chloride and 25% HCl, and pro-content in livers removed 19 hours after halothane extein was precipitated by 5% trichloroacetic acid; the posure compared with nonexposed guinea pigs (Table supernatant was used for calcium determination. The protein 3).…”

Section: Indices Of Hepatic Viability In Perfused Liverssupporting

confidence: 70%

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

FROST¹

1996

Hepatology

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is quantitatively more important. (HEPATOLOGY 1996; To characterize the early events in liver injury pro-23:80-86.) duced by halothane, experiments were performed in genetically susceptible guinea pigs 19 hours after halothane exposure. Serum bile acid concentrations were Many studies have addressed the relationships befourfold increased in halothane-exposed animals com-tween halothane metabolism and liver injury in experipared with controls. In isolated perfused liver experi-mental models. [1][2][3][4][5][6] It is evident that metabolism of haloments, livers from halothane-exposed animals did not thane is usually required, but the manner in which this differ in hepatic oxygen uptake or in perfusion pressure leads to the onset of hepatocellular necrosis a few days at the end of experiments, but bile flow and biliary bile later is not known. The guinea pig model of halothanesalt concentrations were reduced. Hepatic calcium coninduced liver injury is of some interest to the human tent was increased in halothane-exposed guinea pigs counterpart because there is no requirement for induccompared with controls, and further experiments were performed to explore the reason for this. As determined tion of drug-metabolizing enzymes or for deliberate proby infusion of 45 Ca to steady-state perfusate concentra-duction of systemic hypoxia. 7-10 However, it is apparent tions, hepatic calcium clearance was increased in halo-from the temporal development of hepatic necrosis and thane-exposed guinea pigs compared with controls (0.37 the similar severity after single and multiple exposures { 0.06 vs. 0.28 { 0.02 mL/min, P õ .01). Decreased biliary to halothane 7,11 that immunologic mechanisms are unexcretion of calcium was also noted and was entirely likely to be operative in the guinea pig model, as they attributable to reduced bile flow. However, although de-appear to be in humans. Rather, a relationship to halocreased excretion contributed to hepatic accumulation thane metabolism with production of reactive metaboof calcium, it was quantitatively less important than enlites 7,10 and lipid peroxidation 12 or production of hepatic hanced hepatic uptake. As indicated by passage of a boischemia through halothane-induced reduction of helus of horseradish peroxidase from perfusate into bile, hepatic tight junction permeability was increased five-patic blood flow 13 have been proposed as mediating fold after halothane exposure. It is concluded that chole-liver injury. stasis, as exemplified by reduced bile flow, is an earlyAn advantage of the guinea pig model is that the feature of the liver injury produced by halothane in predisposition to hepatotoxicity is a genetically deterguinea pigs and is associated with increased tight junc-mined property that remains constant among individtion permeability. Although the decrease in bile flow ual animals. 8,14 Thus, susceptibility or resistance to contributes to an early increase in hepatic calcium con-halothane-induced liver injury can be characterized, tent, entry of calcium from the perfusi...

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Section: Indices Of Hepatic Viability In Perfused Liverssupporting

confidence: 70%

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

FROST¹

1996

Hepatology

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“…Hepatic calcium content was determined by atomic absorp-Homeostasis. As expected from our earlier study, 9 tion spectrometry, as previously described. 9,26 Liver was ho-there was a threefold increase in total hepatic calcium mogenized in 5% lanthanum chloride and 25% HCl, and pro-content in livers removed 19 hours after halothane extein was precipitated by 5% trichloroacetic acid; the posure compared with nonexposed guinea pigs (Table supernatant was Analysis of Data.…”

supporting

confidence: 70%

“…8,14 Thus, susceptibility or resistance to contributes to an early increase in hepatic calcium con-halothane-induced liver injury can be characterized, tent, entry of calcium from the perfusion compartment animals allowed to recover, and subsequent exposure to halothane used to examine early events during the production of liver damage. We and others 7,9 have re- Westmead, NSW, Australia. Received January 27, 1995; accepted August 11, 1995. after exposure are therefore likely to be related to the As for several types of toxic liver injury, 15-19 massive Presented in part at the Annual Scientific Meeting of the American Associacalcium accumulation is a feature of halothane-induced tion for the Study of Liver Diseases, Chicago, IL, November 1992, and has been published in abstract form (HEPATOLOGY 1992;16:161A).…”

Section: Stasis As Exemplified By Reduced Bile Flow Is An Earlymentioning

confidence: 85%

“…9 It has been suggested that derange-crosis has occurred. In the current study, we noted that hepatic calcium accumulation was increased as early as 19 hours after halothane exposure to susceptible guinea pigs.…”

Section: Stasis As Exemplified By Reduced Bile Flow Is An Earlymentioning

confidence: 99%

“…9 Nonfasted guinea pigs thetized with ketamine (100 mg/kg) and xylacine (20 mg/kg), were anesthetized for 4 hours with 1% halothane delivered the abdomen was opened to expose the liver, and the bile duct in medical air, according to a previously published protocol was canulated with polyethylene tubing (0.86-mm internal that maintained normothermia and appropriate ambient oxy-diameter 1 1.27-mm outer diameter; SP61, from Critchley gen concentrations. 9 At the end of anesthesia, animals were Electrical Products, Sydney, Australia). After ligation of the returned to their cages and allowed to recover.…”

mentioning

confidence: 99%

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Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

et al. 1996

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To characterize the early events in liver injury produced by halothane, experiments were performed in genetically susceptible guinea pigs 19 hours after halothane exposure. Serum bile acid concentrations were fourfold increased in halothane-exposed animals compared with controls. In isolated perfused liver experiments, livers from halothane-exposed animals did not differ in hepatic oxygen uptake or in perfusion pressure at the end of experiments, but bile flow and biliary bile salt concentrations were reduced. Hepatic calcium content was increased in halothane-exposed guinea pigs compared with controls, and further experiments were performed to explore the reason for this. As determined by infusion of 45Ca to steady-state perfusate concentrations, hepatic calcium clearance was increased in halothane-exposed guinea pigs compared with controls (0.37 +/- 0.06 vs. 0.28 +/- 0.02 mL/min, P < .01). Decreased biliary excretion of calcium was also noted and was entirely attributable to reduced bile flow. However, although decreased excretion contributed to hepatic accumulation of calcium, it was quantitatively less important than enhanced hepatic uptake. As indicated by passage of a bolus of horseradish peroxidase from perfusate into bile, hepatic tight junction permeability was increased five-fold after halothane exposure. It is concluded that cholestasis, as exemplified by reduced bile flow, is an early feature of the liver injury produced by halothane in guinea pigs and is associated with increased tight junction permeability. Although the decrease in bile flow contributes to an early increase in hepatic calcium content, entry of calcium from the perfusion compartment is quantitatively more important.

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Halothane-Induced Liver Injury in Outbred Guinea Pigs: Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility

Bourdi

Amouzadeh

Rushmore

et al. 2001

Chem. Res. Toxicol.

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Halothane causes a mild form of liver injury in guinea pigs that appears to model the hepatotoxicity seen in approximately 20% of patients treated with this drug. In previous studies, it was concluded that the increased susceptibility of some outbred guinea pigs to halothane-induced liver injury is not caused by their inherent ability to metabolize halothane to form toxic levels of trifluoroacetylated protein adducts in the liver. In this study, we reevaluated the role of trifluoroacetylated protein adducts in halothane-induced liver injury in guinea pigs. Male outbred Hartley guinea pigs were treated with halothane intraperitoneally. On the basis of serum alanine aminotransferase levels and liver histology, treated animals were designated as being susceptible, mildly susceptible, or resistant to halothane. Immunoblot studies with the use of anti-trifluoroacetylated antibodies showed that susceptible guinea pigs for the most part had higher levels of trifluoroacetylated protein adducts in the liver 48 h after treatment with halothane than did less susceptible animals. In support of this finding, the level of trifluoroacetylated protein adducts detected immunochemically in the sera of treated guinea pigs correlated with sera levels of alanine aminotransferase activity. In addition, the levels of cytochrome P450 2A-related protein but not those of other cytochrome P450 isoforms, measured by immunoblot analysis with isoform-specific antibodies, correlated with the amount of trifluoroacetylated protein adducts detected in the livers of guinea pigs 8 h after halothane administration. The results of this study indicate that the susceptibility of outbred guinea pigs to halothane-induced liver injury is related to an enhanced ability to metabolize halothane in the liver to form relatively high levels of trifluoroacetylated protein adducts. They also suggest that cytochrome P450 2A-related protein might have a major role in catalyzing the formation of trifluoroacetylated protein adducts in the liver of susceptible guinea pigs. Similar mechanisms may be important in humans.

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Altered Hepatic Calcium Homeostasis in Guinea Pigs with Halothane-Induced Hepatotoxicity

Cited by 7 publications

References 0 publications

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Impaired bile flow and disordered hepatic calcium homeostasis are early features of halothane-induced liver injury in guinea pigs

Halothane-Induced Liver Injury in Outbred Guinea Pigs: Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility

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