Pleiotropic drug resistance in hepatocytes induced by carcinogens administered to rats

B. I. Carr

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The effect of hepatocarcinogen administration in vivo on the induction of pleiotropic drug resistance was studied in primary monolayer cultures of adult rat hepatocytes using a cytotoxicity assay in vitro. Dietary 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, aflatoxin B1, ethionine, and diethylnitrosamine rapidly induced resistance to doses of Adriamycin, methotrexate, cycloheximide, and aflatoxin B1 which were cytocidal to normal hepatocytes from untreated rats. Up to 95% of some hepatocyte preparations became drug resistant before any new hepatocyte phenotypes could proliferate. Drug resistance was measured at 24 h after initiation of 2-acetylaminofluorene feeding and remained stable throughout the 16 wk of carcinogen exposure. When limited carcinogen exposure was followed by a return to a basal non-carcinogen-containing diet for many months, the hepatocytes in the resultant hepatocellular carcinomas also displayed pleiotropic drug resistance, and the cells of the peritumorous liver did so to a lesser extent. Drug resistance was not induced by chronic administration of the tumor promoters phenobarbital, choline-deficient diet, phorbol, nor with 2,3,7,8-tetrachlorodibenzo-p-dioxin, but was induced to a variable extent by three hepatotoxins (ethanol, methotrexate, carbon tetrachloride). Whereas the early appearing drug resistance appears to be an adaptation of the liver to the presence of a toxic carcinogen, the late resistance which does not disappear after withdrawal of the inducing carcinogen may be a constitutive characteristic of chemically induced hepatocellular carcinomas.

Original languageEnglish
Pages (from-to)5577-5583
Number of pages7
JournalCancer Research
Issue number21
Publication statusPublished - 1987

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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