Genotoxic effects of p-aminophenol in Chinese hamster ovary and mouse lymphoma cells: results of a multiple endpoint test.
p-Aminophenol (PAP), a metabolite of aniline and acetaminophen, has been reported to be mutagenic in the L5178Y mouse lymphoma assay, but not in the CHO/HGPRT assay. In the present study, the effects of PAP in these two cells lines were examined to determine if the difference in activity is related to an intrinsic difference in the cell lines. CHO and L5178Y tk +/- mouse lymphoma cells were treated with PAP for 4 hr and assayed for 3 genetic endpoints: gene mutation at the HGPRT or TK locus, respectively; chromosomal aberrations at approximately 20 hr after initiation of treatment; and single-strand DNA breaks as detected by the single cell electrophoresis assay immediately after treatment. All treatments were conducted in the absence of S9. There was a dose-related, significant increase in TFT-resistant mouse lymphoma cells at dose levels that reduced survival to < or = 50% of concurrent controls. In CHO cells, however, there was no increase in thioguanine-resistant cells at dose levels that reduced cell survival to < 20%. These results are consistent with published reports on PAP. While the CHO cells were slightly more resistant to the toxic effects of PAP, the dose levels used in the two cell lines did not differ by more than 2-fold. At equivalent survival levels, PAP induced a significant (up to 20% aberrant cells) number of aberrations, primarily complex rearrangements, in both cell lines. In the single cell electrophoresis assay, there was a reproducible dose-related increase in cells with single-strand DNA breaks with both the L5178Y cells and the CHO cells. The induction of single-strand breaks and chromosome aberrations by PAP suggests that, mechanistically, PAP produces similar genetic damage in both CHO and L5178Y cell lines, but intrinsic differences between assay systems are responsible for the divergent gene mutation results.
Majeska
J B
JB
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA.
Holden
H E
HE
D000627:Aminophenols / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells / Q000166:cytology / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004277:DNA, Single-Stranded; D004305:Dose-Response Relationship, Drug; D004586:Electrophoresis; D005797:Genes, araC / Q000187:drug effects / Q000235:genetics; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000627:Aminophenols; D004277:DNA, Single-Stranded; D007041:Hypoxanthine Phosphoribosyltransferase; C026729:4-aminophenol