Effect of pH on the neoplastic transformation of normal human skin fibroblasts by N-hydroxy-1-naphthylamine and N-hydroxy-2-naphthylamine.
The conversion of urinary N-hydroxy arylamines to carcinogenic electrophiles under mildly acidic conditions in the bladder lumen has been proposed as an essential step in arylamine-induced urinary bladder carcinogenesis. To test the hypothesis that extracellular generation of an ultimate carcinogenic species can initiate a neoplastic event normal human fibroblasts were exposed to N-hydroxy-1- and 2-naphthylamine (N-HO-1-NA and N-HO-2-NA) at pH 5 and pH 7. With both compounds, anchorage independent growth of transformed cells in soft agar were enhanced 3- to 7-fold in the pH 5 incubations. Injection of the N-HO-1-NA and N-HO-2-NA-transformed cells into nude mice resulted in tumors in 1/8 and 2/7 animals, respectively. In a control experiment, no differences in transformation of these cells by aflatoxin B1 were observed between pH 5 and pH 7 exposures. Thus, the results are consistent with the hypothesis that ultimate carcinogenic electrophiles, generated extracellularly, can enter an intact cell and induce neoplasia. Alternatively, the possibility of a local intracellular acidic environment near the cell surface and its role in the generation of a reactive electrophile leading to urinary bladder carcinogenesis is discussed.
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005347:Fibroblasts; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009281:Naphthalenes / Q000494:pharmacology*
D002273:Carcinogens; D009281:Naphthalenes; C017893:N-hydroxy-1-naphthylamine; D015057:1-Naphthylamine; D015081:2-Naphthylamine; C019424:N-hydroxy-2-naphthylamine