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© 1986 Oxford University Press

research-article

Murine Acetaminophen Hepatotoxicity: Temporal Interanimal Variability in Plasma Glutamic-Pyruvic Transaminase Profiles and Relation to in Vivo Chemical Covalent Binding1

Peter G. Wells2 and Esther C.A. To3

Faculty of Pharmacy. University of Toronto 19 Russell Street. Toronto. Ontario, Canada M5S IAI

Murine Acetaminophen Hepatotoxicity: Temporal Interanimal Variability in Plasma Glutamic-Pyruvic Transaminase Profiles and Relation to in Vivo Chemical Covalent Binding1 Peter G. Wells2 and Esther C. A. To3 Faculty of Pharmacy. University of Toronto. 19 Russell Street. Toronto. Ontario, Canada M5S IAI Murine Acetaminophen Hepatotoxicity: Temporal Interanimal Variability in Plasma Glutamic- Pyruvic Transaminase Profiles and Relation to in Vivo Chemical Covalent Binding. Wells, P. G., and To, E. C. A. (1986). Fundam Appl. Toxicol. 7, 17–25. The hepatotoxicity of acetaminophen is thought to be dependent upon its enzymatic bioactivation to a reactive intermediary metabolite which binds covalently to essential cellular macromolecules, thereby causing cellular death. Traditional in vivo methods using smaller mammals are mechanistically restrictive in that measures of hepatotoxicity, such as plasma glutamic-pyruvic transaminase (GPT), and chemical. I covalent binding to hepatocellular protein are performed at different times in separate groups of animals. We developed a microanalytical technique which allowed repetitive plasma GPT sampling from individual mice, followed by delayed determination of covalent binding in the same mouse 36 hr after acetaminophen administration. Diethyl ether anesthesia was used to enhance acet-aminophen hepatotoxicity. The repetitive sampling technique permitted an accurate determination of the peak GPT concentration, which exhibited a marked interanimal variability in the time of occurrence. Individual peak GPT concentrations correlated with the respective covalent binding of acetaminophen in each mouse (r=0.82, p < 0.05), while the traditional method using a fixed % sampling time (24 hr) failed to correlate (r=0.50, p > 0.05). Ether produced a 39-fold enhancement in the severity of acetaminophen hepatotoxicity; however, a single, fixed-time sample taken at either 12 or 24 hr produced a substantial and inconsistent over- or underestimate of this toxicologic enhancement. This study shows that chemical hepatotoxicity as reflected by plasma GPT concentration cannot be quantified accurately by a single blood sample obtained from a given animal, regardless of the chosen sampling time. An accurate determination of the peak plasma GPT concentration in any single animal requires repetitive blood sampling, preferably in the absence of general anesthesia.


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