Species differences in cytotoxic and genotoxic effects of phenacetin and paracetamol in primary monolayer cultures of hepatocytes.
The cytotoxic and genotoxic effects of phenacetin and paracetamol were examined in monolayer cultures of hepatocytes isolated from the mouse, hamster, rat and guinea pig. No marked increase in unscheduled DNA synthesis (UDS) after exposing hepatocytes from any of the species to phenacetin was observed. At cytotoxic concentrations of paracetamol, an increased UDS in mouse hepatocytes in vitro was observed. Pretreatment of the mice by inducers of drug-metabolizing enzymes, such as 3-methylcholanthrene and Aroclor 1254, lowered the concentration threshold for the toxic responses. With rat hepatocytes only a minor increase in UDS was noted, while with hepatocytes from hamsters and guinea pigs in fact a decrease was seen. The narrow range observed between the cytotoxic and genotoxic effects of paracetamol makes it difficult to predict whether the initial DNA damage could lead to a mutation or whether the cells will die before the mutation is expressed. With respect to the cytotoxic effects, hamster hepatocytes were found to be most susceptible to paracetamol, followed by mouse, while rat and guinea pig were less affected. These data were in accordance with in vivo findings (Davis et al., 1974), indicating the potential value of hepatocyte culture when screening for possible liver toxic substances.
Holme
J A
JA
Søderlund
E
E
D000082:Acetaminophen; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects; D006168:Guinea Pigs; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D010615:Phenacetin; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014343:Trypan Blue
D000082:Acetaminophen; D004247:DNA; D007770:L-Lactate Dehydrogenase; D010615:Phenacetin; D014343:Trypan Blue