The nongenotoxic hepatocarcinogens diethylhexylphthalate and methylclofenapate induce DNA synthesis preferentially in octoploid rat hepatocytes.
Diethylhexylphthalate (DEHP), a rodent carcinogen, and 1,4-dichlorobenzene (DCB), a noncarcinogen in rat liver, are potent hepatomitogens. We have reported previously that 7-day dosing with DEHP induced a higher bromodeoxyuridine labeling index (LI) in binuclear octoploid (2x4N) rat hepatocytes than did DCB, suggesting that induction of DNA synthesis in 2x4N hepatocytes might represent a more substantial carcinogenic risk. We compared 2 additional rodent hepatocarcinogens, methylclofenapate (MCP) and phenobarbitone, with ethylene thiourea (ETU), a noncarcinogenic hepatomitogen in rat. All 3 chemicals increased hepatic LI; the 8N population had the highest LI, but only the carcinogens increased LI in the 2x4N and 4N populations. To identify the target population for induction of DNA synthesis, we used a 1-hour pulse label at the peak of induction. The results were consistent with the 7-day data, and again the highest LI was in the 8N population. The nongenotoxic rodent carcinogens MCP and DEHP induced a significant increase in the LI in the 2x4N population, whereas ETU and DCB did not. These data support the hypothesis that increased DNA synthesis within the minority 2x4N population may be more significant for subsequent hepatocarcinogenesis.
AstraZeneca Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom. sue.hasmall@ctl.zeneca.com
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Hasmall
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Roberts
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000963:Antimetabolites; D001973:Bromodeoxyuridine; D002273:Carcinogens / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects; D002992:Clofenapate / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis*; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010672:Phenytoin / Q000494:pharmacology; D011123:Polyploidy; D051381:Rats; D011916:Rats, Inbred F344
D000927:Anticonvulsants; D000963:Antimetabolites; D002273:Carcinogens; D002992:Clofenapate; D010672:Phenytoin; D004247:DNA; D004051:Diethylhexyl Phthalate; D001973:Bromodeoxyuridine