Mutagenicity of carcinogenic nitrosamines when activated by hamster and human pancreatic duct epithelial cells.
We have measured the ability of pancreatic duct epithelial cells (DEC) from Syrian hamsters and humans and CK cells, immortalized hamster DEC, to metabolize chemical carcinogens to species that were mutagenic in S. typhimurium TA98 and in V79 cells. The chemicals were N-nitrosobis(2-oxopropyl)amine (BOP), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The ability of ethanol (EtOH) to modify the metabolizing efficiency was also measured. When an S9 preparation from EtOH-treated CK cells was used to metabolize NNK the number of revertants was 271 +/- 73 compared with 17 +/- 2 when the S9 from control CK cells was used. When hamster DEC were used there was no increase in the mutation frequency for BOP in V79 cells (64 +/- 20 mutants/10(6) survivors per mumol) when EtOH-DEC were used. However, the mutation frequencies of NNK and PhIP rose when the EtOH-treated DEC were used from 62 +/- 31 to 198 +/- 28 mutants/10(6) survivors per mumol for NNK and from 94 +/- 25 to 166 +/- 25 mutants/10(6) survivors per mumol for PhIP. A similar result was obtained when human DEC were used, i.e. no change in BOP mutagenicity and a slight increase in PhIP mutagenicity, from 34 +/- 14 to 65 +/- 12 mutants/10(6) survivors per mumol. There were large increases in the mutagenicity of NNK with each of the three samples of human DEC that were used, from 75 +/- 0 to 213 +/- 38, 75 +/- 13 to 175 +/- 25 and 38 +/- 13 to 285 +/- 25 mutants/10(6) survivors per mumol. The EtOH treatment regimen that was used more closely mimicked chronic exposure at low concentrations in vivo. These data show that hamster DEC are capable of metabolizing NNK, which is carcinogenic in these cells in vivo. Furthermore, human DEC metabolized NNK as efficiently as hamster DEC.
Kolar
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Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Lawson
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D000293:Adolescent; D000328:Adult; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D002478:Cells, Cultured; D002648:Child; D003043:Cocarcinogenesis; D006224:Cricetinae; D004847:Epithelial Cells / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D009152:Mutagenicity Tests; D009153:Mutagens; D009602:Nitrosamines; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; D009602:Nitrosamines; D000431:Ethanol; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine