title: Pleiotropic drug resistance in hepatocytes induced by carcinogens administered to rats.
abstract: 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.
mesh_terms: D015073:2-Acetylaminofluorene; D000222:Adaptation, Physiological; D000818:Animals; D002273:Carcinogens; D004351:Drug Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008749:Methyldimethylaminoazobenzene; D011230:Precancerous Conditions / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000032:analysis
chemical_list: D002273:Carcinogens; D008749:Methyldimethylaminoazobenzene; D015073:2-Acetylaminofluorene; D005723:gamma-Glutamyltransferase