Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes.
Most of the experiments studying acetaminophen (APAP) induced hepatotoxicity were performed using moue as model specie, right because its high sensitivity. While the toxic responses can be called forth easily in mice, the human relevancy of these results is questionable. In this study human, rat, and mouse primary hepatocytes were treated with increasing concentrations of APAP, and cell viability was measured by MTT cytotoxicity assay. Pronounced interspecies differences were obtained in cell viability following 24h of APAP treatment starting at 24h after seeding (EC50: 3.8mM, 7.6mM, and 28.2mM, in mouse, rat, and human hepatocyte culture, respectively). The longer time of culturing highly increased the resistance of hepatocytes of all species investigated. In rat hepatocyte culture EC50 values were 6.0mM, 12.5mM, and 18.8mM, when starting APAP treatment after 24, 48, and 72 h of seeding. Although N-acetylbenzoquinoneimine, a minor metabolite of APAP, which is mainly formed by CYP2E1 at high APAP concentration in every species studied, is thought to initiate the toxic processes, no correlation was found between CYP2E1 activities and hepatocyte sensitivity of different species. We conclude that the toxicity induced by APAP overdose highly depends on the animal model applied.
Jemnitz
Katalin
K
Department of Biochemical Pharmacology, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, PO Box. 17, H-1525 Budapest, Hungary. jemnitz@chemres.hu <jemnitz@chemres.hu>
Veres
Zsuzsa
Z
Monostory
Katalin
K
Kóbori
László
L
Vereczkey
László
L
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D013045:Species Specificity; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1