Acetaminophen metabolism, cytotoxicity, and genotoxicity in rat primary hepatocyte cultures.
Acetaminophen (APAP) metabolism, cytotoxicity, and genotoxicity were measured in primary cultures of rat hepatocytes. Although 3 mM APAP caused a slight increase in cellular release of lactate dehydrogenase into the culture medium, cellular glutathione concentration (an index of APAP metabolism) was reduced by 50%. APAP at 7 mM was significantly more toxic to these hepatocytes and had a similar but more marked effect on glutathione concentrations. In spite of its cytotoxicity, neither dose of APAP stimulated DNA repair synthesis when monitored by the rate of incorporation of [3H]thymidine into DNA following exposure to APAP. Thus, although APAP has been shown to be both hepato- and nephrotoxic in several in vivo and in vitro systems, the reactive toxic metabolite of APAP is not genotoxic in rat primary hepatocyte cultures.
D000082:Acetaminophen / Q000378:metabolism* / Q000633:toxicity; D016604:Aflatoxin B1; D000348:Aflatoxins / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D003124:Colorimetry; D003603:Cytotoxins / Q000378:metabolism* / Q000633:toxicity; D004247:DNA / Q000032:analysis; D004260:DNA Repair / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
D000348:Aflatoxins; D003603:Cytotoxins; D014316:Tritium; D000082:Acetaminophen; D004247:DNA; D016604:Aflatoxin B1; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D013936:Thymidine