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© 1991 Oxford University Press

research-article

Recovery of hyperplastic responsiveness in rat liver after dosing with the peroxisome proliferator methylclofenapate

J.A. Styles, M.D. Kelly, C.R. Elcombe, A. Bybee and N.R. Pritchard

Imperial Chemical Industrial plc, Central Toxicololgy Laboratory Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK

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 ({small tilde}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 {small tilde}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 {small tilde}10% in annuals dosed continuously with MCP, to {small tilde}11.4% after 28 days interruption, 17% after 35 days and control levels ({small tilde}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 ({small tilde}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.


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