Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient Xpa mice.
Chronic use of phenacetin-containing analgesics has been associated with the development of renal cancer. To establish genotoxicity as a possible cause for the carcinogenic effect of phenacetin, we exposed wild type and DNA repair deficient Xpa-/- and Xpa-/-/Trp53+/- mice (further referred as Xpa and Xpa/p53 mice, respectively), carrying a reporter lacZ gene, to 0.75% (w/w) phenacetin mixed in feed. Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds. Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice. A minor response was found in liver, whereas no lacZ mutation induction was observed in the spleen of these animals. Interestingly, the observed phenacetin-induced mutant frequencies were higher in male than those found in female mice. This gender difference is probably due to a difference in metabolic rate. Phenacetin-induced mutations mainly consisted of point mutations rather than deletions. The mutational spectra in the kidney of treated WT and Xpa mice were quite similar. Taken together, these results demonstrate that the human carcinogen phenacetin acts as a weak genotoxic agent in an in vivo mouse model system.
Luijten
Mirjam
M
Laboratory of Toxicology, Pathology and Genetics, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands. Mirjam.Luijten@rivm.nl
Speksnijder
Ewoud N
EN
van Alphen
Niels
N
Westerman
Anja
A
Heisterkamp
Siem H
SH
van Benthem
Jan
J
van Kreijl
Coen F
CF
Beems
Rudolf B
RB
van Steeg
Harry
H
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D010615:Phenacetin / Q000633:toxicity*; D012727:Sex Characteristics; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
D002273:Carcinogens; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D010615:Phenacetin