Murine acetaminophen hepatotoxicity: temporal interanimal variability in plasma glutamic-pyruvic transaminase profiles and relation to in vivo chemical covalent binding.
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 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 acetaminophen 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 less than 0.05), while the traditional method using a fixed sampling time (24 hr) failed to correlate (r = 0.50, p greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D013997:Time Factors
D000082:Acetaminophen; D000410:Alanine Transaminase