Halothane hepatitis: damage to peripheral blood mononuclear cells produced by electrophilic drug metabolites is Ca(2+)-dependent

Journal of Gastroenterology and Hepatology
L FrostG C Farrell

Abstract

Peripheral blood mononuclear (PBM) cells from patients with halothane hepatitis are unusually susceptible to damage from phenytoin metabolites generated by an in vitro drug metabolising system. In order to provide more information about the nature of this susceptibility factor, the effect of removing calcium ions (Ca2+) from the incubation medium of the test system was examined. Phenytoin metabolites were generated by incubating phenytoin with beta-naphthoflavone-induced rat liver microsomes in the presence of 1,1,1-trichloropropene oxide (TCPO), an epoxide hydrase inhibitor. When PBM cells from patients who had recovered from halothane hepatitis were incubated in this system and then maintained in Ca(2+)-containing tissue culture medium (without alpha-tocopherol) for 16 h, cell death, as measured by trypan blue exclusion, was greatly increased (53% and 78% at 0.06 mmol/l and 0.12 mmol/l phenytoin, respectively) compared with control incubations (TCPO omitted). Removal of Ca2+ from the tissue culture medium effectively abolished reactive metabolite-induced cell death. Resting cytosolic free Ca2+ concentration in PBM cells was also measured using the quin-2 fluorescence method and total Ca2+ content was measured by atomic absorp...Continue Reading

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Citations

Jan 1, 1996·Journal of Gastroenterology and Hepatology·L S ChenS D Lee
Mar 1, 1991·Journal of Gastroenterology and Hepatology·K H LaiS D Lee
Mar 1, 1995·The British Journal of Nutrition·G R CorazzaG Gasbarrini
Apr 28, 2006·Emotion·Alexander J ShackmanRichard J Davidson
Mar 8, 2000·The Journal of Social Psychology·K D ParkerG Weaver

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