Recovery of hyperplastic responsiveness in rat liver after dosing with the peroxisome proliferator methylclofenapate.
Methylclofenapate (MCP) was administered daily by gavage (25 mg/kg) for 7 days to groups of adult male rats. Dosing was interrupted for 28, 35, 56, 70 or 84 days and then resumed (25 mg/kg by gavage at 0 and 24 h). During the second period of dosing animals were killed in groups of three at 6, 12, 18, 24, 30, 36, 42 and 48 h after the resumption of dosing. Hepatocytes in S-phase, labelled with bromodeoxy-uridine, were analysed by flow cytometry, cell sorting and microscopy. It was observed that total S-phase activity was just significantly elevated (approximately 20% of maximum) over corn oil controls after an interval of 28 days between initial and subsequent dosing periods. After an interval of 35 days total S-phase activity was approximately 65% of maximum, and full hyperplastic responsiveness, equal to that observed in naive animals given MCP, was detected after interruptions in dosing of 56, 70 and 84 days. The recovery of S-phase responsiveness during the interruptions in dosing was accompanied by an increase in the proportion of 2 X 2N hepatocytes from approximately 10% in animals dosed continuously with MCP, to approximately 11.4% after 28 days interruption, 17% after 35 days and control levels (approximately 20%) after 56, 70 and 84 days. Irrespective of the magnitude of the hyperplasia elicited by the second period of dosing with MCP, the proportion of 2 X 2N cells was reduced to the same levels as those observed in animals dosed continuously with MCP (approximately 10%). Very low S-phase activity (0.05%) was observed in animals dosed continuously with MCP, this level of activity being similar to that in animals given corn oil continuously.
Styles
J A
JA
Imperial Chemical Industries plc, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire UK.
Kelly
M D
MD
Elcombe
C R
CR
Bybee
A
A
Pritchard
N R
NR
D000818:Animals; D002992:Clofenapate / Q000494:pharmacology*; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D006965:Hyperplasia / Q000139:chemically induced; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D016196:S Phase / Q000187:drug effects; D013997:Time Factors
D002992:Clofenapate; D004247:DNA