A species comparison of acute hyperplasia induced by the peroxisome proliferator methylclofenapate: involvement of the binucleated hepatocyte.
The acute hyperplastic response induced by methylclofenapate (MCP) was studied in several rodent species with different responsiveness to the hypertrophic and hyperplastic effects caused by this chemical. The species, in descending order of responsiveness, were: mouse, rat, hamster and guinea-pig, the latter species being non-responsive. Animals were dosed at daily intervals with MCP (25, 12 or 5 mg/kg by gavage) and killed at intervals from 12 h to 240 h. The parameters of ploidy, nuclearity and DNA synthesis were examined in isolated hepatocytes. The hyperplastic response elicited by MCP in rodent livers as detected by the occurrence of S-phase cells, was almost exclusively confined to the 2 x 2N (binucleated) hepatocyte population. At the same time the proportion of 2 x 2N cells was reduced in a time and dose-dependent manner, while the fraction of 4N cells increased. These observations indicate that the 2 x 2N cells responding to MCP undergo S-phase followed by amitotic cytokinesis to form 4N cells. The response in rats, mice and hamsters was quantitatively different but qualitatively similar, while the guinea-pig was non-responsive. In a given responsive species the areas under the curves are similar for different doses, indicating that the size of the responsive population is limited. The data also indicate that although the response in the mouse was greater than in the rat, because the total number of responsive 2 x 2N cells is larger, the percentage of responsive 2 x 2N cells is higher in the rat than in the mouse. The ploidy analysis reveals that there is no detectable change in the ratio of (4N + 2 x 2N):2N hepatocytes, but only 1-2% change would be expected, despite the number of 4N cells produced, due to the increase in total cell number.
Styles
J A
JA
Imperial Chemical Industries PLC, Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Kelly
M
M
Pritchard
N R
NR
Elcombe
C R
CR
D000818:Animals; D002087:Butyrates / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D002467:Cell Nucleus / Q000648:ultrastructure; D002992:Clofenapate / Q000633:toxicity*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008830:Microbodies / Q000187:drug effects; D011003:Ploidies; D051381:Rats; D013045:Species Specificity
D002087:Butyrates; D002992:Clofenapate