International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.
During the last years, several reports have indicated genotoxic effects of paracetamol, a widely used non-prescription analgesic and antipyretic drug. Thus, a careful evaluation of a possible genotoxic effect related to paracetamol use is warranted. Studies in vitro and in vivo indicate that the reactive metabolite of paracetamol can bind irreversibly to DNA and cause DNA strand breaks. Paracetamol inhibits both replicative DNA synthesis and DNA repair synthesis in vitro and in experimental animals. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. On the other hand, a co-mutagenic effect of paracetamol has been reported. Furthermore, paracetamol increases the frequency of chromosomal damage in mammalian cell lines, isolated human lymphocytes and experimental animals. Two independent studies have shown an increase in chromosomal damage in lymphocytes of human volunteers after intake of therapeutic doses of paracetamol, whereas a third study was negative. Paracetamol-induced chromosomal damage appears to be caused by an inhibition of ribonucleotide reductase. This indicates that a threshold level for the paracetamol-induced chromosomal damage may exist. Genotoxic effects of paracetamol have, however, been demonstrated both in vitro and in vivo at or near therapeutic concentrations. The data indicate that the use of paracetamol may contribute to an increase in the total burden of genotoxic damage in man. Thus, there may be a need to evaluate the therapeutic benefit of paracetamol, taking into consideration not only its potential to induce acute and chronic organ damage, but also genotoxic effects.
Rannug
U
U
Department of Genetic and Cellular Toxicology, Stockholm University, Sweden.
Holme
J A
JA
Hongslo
J K
JK
Srám
R
R
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D000085:Acetates / Q000633:toxicity; D019342:Acetic Acid; D000328:Adult; D000627:Aminophenols / Q000633:toxicity; D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D016227:Benzoquinones / Q000633:toxicity; D001711:Biotransformation; D002460:Cell Line; D002648:Child; D002875:Chromosomes / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D005260:Female; D006801:Humans; D007097:Imines / Q000633:toxicity; D009152:Mutagenicity Tests; D010944:Plants / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D012377:Rodentia
D000085:Acetates; D000627:Aminophenols; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C017372:N-hydroxyacetaminophen; D012264:Ribonucleotide Reductases; C028473:N-acetyl-4-benzoquinoneimine; D019342:Acetic Acid; C026729:4-aminophenol