Inhibitory effects of paracetamol on DNA repair in mammalian cells.
Paracetamol blocks DNA replication by inhibiting deoxyribonucleotide (dNTP) synthesis and may therefore also interfere with DNA repair. In the present work various mammalian cell types were treated with genotoxic agents and allowed to repair in the presence or absence of paracetamol. Alkaline elution was used to assay DNA single-strand breaks plus alkali-labile sites (= SSBs). Resting human mononuclear blood cells (MNC) exposed to 4-nitroquinoline N-oxide (NQO, 3 microM) plus 0.3 mM paracetamol contained twice as many DNA SSBs compared to MNC exposed to NQO alone, and the level of SSBs decreased more slowly during repair in the presence of paracetamol. Deoxyribonucleosides reversed the effects of paracetamol. SSBs induced by MMS or X-rays (2.6 Gy) were not increased by paracetamol. Resting and growth-stimulated MNC, HL-60 cells, rat hepatocytes and human fibroblasts exposed to UV-C (3-12 J/m2) showed varying levels of transient SSBs formed during repair but these were consistently higher in the presence of paracetamol (0.3-1 mM). In rat testicular cells SSBs were induced by NQO and the levels were further increased in the presence of paracetamol, whereas after UV almost no SSBs were detected during repair. The cell-type specific levels of transient SSBs after UV did not correlate with the rate of incision of DNA lesions, measured as the rate of SSB accumulation in the presence of repair inhibitors Ara C plus hydroxyurea. Transient SSBs were present in resting MNC for at least 24 h after UV and paracetamol increased these breaks 4-fold however the overall rate of removal of excisable photodamage during repair did not appear to be reduced by the presence of paracetamol. The present data indicate that paracetamol interferes with nucleotide excision repair in several mammalian cell types. This constitutes a mechanism by which paracetamol may contribute to genotoxicity in humans.
Brunborg
G
G
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Holme
J A
JA
Hongslo
J K
JK
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D008297:Male; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014466:Ultraviolet Rays
D003561:Cytarabine; D000082:Acetaminophen; D015112:4-Nitroquinoline-1-oxide; D008741:Methyl Methanesulfonate