Relationship of hepatocarcinogenicity and hepatocellular proliferation induced by mutagenic noncarcinogens vs carcinogens. II. 1- vs 2-nitropropane.
2-Nitropropane (2-NP) is mutagenic in a number of short-term mutagenicity assays in vitro and in vivo, and is a potent hepatocarcinogen in rats. A structural isomer, 1-nitropropane (1-NP), is mutagenic in V79 cells and can induce unscheduled DNA synthesis in rat hepatocytes, yet did not induce tumors in rats following chronic exposure. We examined the correlation of cell proliferation and hepatocarcinogenesis induced by this mutagenic noncarcinogen-carcinogen pair in a rat liver proliferation model. Rats were exposed to gavage doses of 0.5, 1, or 2 mmol/kg of 1-NP or 2-NP daily for 10 days; the highest two dose groups were similar to the doses used in the carcinogenesis bioassay. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. Animals exposed to the vehicle exhibited a labeling index (LI) of approximately 1.9% and animals exposed to CCL4 had a LI of approximately 30%. Rats exposed to the hepatocarcinogen 2-NP exhibited a dose-related increase in LI to 6.3 and 11% at the 1 and 2 mmol/kg doses, respectively, and no increase above control at the 0.5 mmol/kg exposure level. Animals exposed to the noncarcinogenic isomer 1-NP showed no statistically significant increase in LI above controls at any dose level tested. Serum chemistries were consistent with mild to moderate decreases in hepatocellular function, cholestasis, and necrosis following 2-NP exposure, but only minimal effects were observed, probably due to slight dehydration resulting from 1-NP exposure. These data indicate a positive association between increased cell proliferation and hepatocarcinogenesis induced by these two nitropropane isomers.
Cunningham
M L
ML
Experimental Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Matthews
H B
HB
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D009595:Nitroparaffins / Q000009:adverse effects; D011407:Propane / Q000009:adverse effects / Q000031:analogs & derivatives; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009153:Mutagens; D009595:Nitroparaffins; C035314:1-nitropropane; D002251:Carbon Tetrachloride; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D001973:Bromodeoxyuridine; C016617:2-nitropropane; D011407:Propane