Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase

Hongslo, Jan K.; Bjørge, Christine; Schwarze, Per E.; Brøgger, Anton; Mann, Graham J.; Thelander, Lars; Holme, Jørn A.

doi:10.1093/mutage/5.5.475

Cited by 53 publications

(27 citation statements)

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“…The drug directly inhibits ribonucleotide reductase, which reduces cell growth by stopping DNA replication (25). Then, the relative number of cells in the S phase increases (25), as we observed after exposure of mIMCD3 cells to APAF (Figs.…”

Section: Discussion Nsaids and Caffeine Are Directly Toxic To Imcd Cementioning

confidence: 61%

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Rocha

Michea

Peters

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by Ϸ50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G1 and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.acetaminophen ͉ aspirin ͉ salicylic acid ͉ indomethacin ͉ caffeine

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Section: Discussion Nsaids and Caffeine Are Directly Toxic To Imcd Cementioning

confidence: 61%

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Rocha

Michea

Peters

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…However, APAP, has an additional toxic effect that may be more pertinent to the toxicity that we observe. The drug directly inhibits ribonucleotide reductase, which reduces cell growth by stopping DNA replication (Hongslo et al, 1990). Then, the relative number of cells in S phase increases (Hongslo et al, 1990), as we observed following exposure of mIMCD3 cells to APAP (Rocha et al, 2001).…”

Section: Discussionmentioning

confidence: 70%

“…Treating mice with increasing doses of APAP for 8 days increases hepatocellular proliferation 4-fold (Shayiq et al, 1999). Reports of decreased proliferation include that APAP produces cell cycle block in Hepa 1-6 cells (Boulares et al, 1999) and HL-60 cells (Wiger et al, 1997), reduces replicative DNA synthesis in mouse mammary tumor cells (Hongslo et al, 1990), and reduces proliferation of HepG2 cells (Dai and Cederbaum, 1995) It has not been clear what factors deter- mine whether APAP will increase or decrease the cell number, but the rate of proliferation and DNA replication apparently is important in p1rIMCD cells. It would be of interest to know whether high levels of APAP increase the otherwise slow rate of proliferation of renal inner medullary cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…APAP arrested most cells in the late G 1 and S phase and produced a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAP is reported to inhibit the synthesis of DNA (Hongslo et al, 1990) and cause chromosomal aberrations (Brunborg et al, 1995) due to inhibition of ribonucleotide reductase. Such effects of APAP might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.…”

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confidence: 99%

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Toxicity of Acetaminophen, Salicylic Acid, and Caffeine for First-Passage Rat Renal Inner Medullary Collecting Duct Cells

Cai¹,

Dmitrieva²,

Michea³

et al. 2003

J Pharmacol Exp Ther

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Chronic excess ingestion of nonsteroid anti-inflammatory drugs causes renal medullary necrosis. Previously, using an immortalized line of mouse inner medullary collecting ducts cells (mIMCD3), we found that acetaminophen, salicylic acid, and caffeine are toxic, and the effects of acetaminophen and caffeine are strongly additive. Furthermore, toxicity was greater in proliferating than in nonproliferating cells. Important limitations were that mIMCD3 cells do not readily tolerate the high concentrations of salt and urea normally present in renal inner medullas and proliferate much more rapidly than inner medullary cells in vivo. Thus, these cells may not serve as an appropriate model for the in vivo IMCD. The present studies address these limitations by using passage-1 rat inner medullary collecting duct (p1rIMCD) cells, which tolerate high salt and urea and become contact inhibited when confluent. At 640 mOsmol/kg (the lowest normal inner medullary osmolality), the drugs, singly and in combination, reduce the number of proliferating (i.e., subconfluent) p1rIMCD cells more than they do confluent cells. Effects of acetaminophen and caffeine are strongly additive. Addition of as little as 0.1 mM caffeine significantly enhances the toxicity of acetaminophen plus salicylic acid. With confluent cells at 640 mOsmol/kg and very slowly growing cells at 1370 mOsmol/kg, combinations of drugs that include acetaminophen increase proliferation, accompanied by DNA damage and apoptosis. We conclude that these drugs are toxic to renal inner medullary collecting duct cells under the conditions of high osmolality normally present in the inner medulla, that combinations of the drugs are more toxic than are the drugs individually, and that the toxicity includes induction of proliferation of these cells that are otherwise quiescent in the presence of high osmolality.Excessive consumption of mixtures of nonsteroidal antiinflammatory drugs (NSAIDs) over a long period of time can cause renal disease, characterized by papillary necrosis and scarring ([No Authors Listed], 1984). The patients have progressive renal failure and are susceptible to the subsequent development of uroepithelial tumors. Combination of NSAIDs, often including caffeine, and chronic antidiuresis were implicated in the toxicity.In an effort to investigate this toxicity, we previously (Rocha et al., 2001) tested effects of salicylic acid (SA), acetaminophen (APAP), and caffeine on mouse renal inner medullary collecting duct (mIMCD3) cells (Rauchman et al., 1993). We found that when mIMCD3 cells are subconfluent, 0.5 mM SA or APAP reduces the number of viable cells by approximately 50%. The drugs have less effect on confluent cells, which are proliferating more slowly. We speculated that the much slower turnover of IMCD cells in vivo (SheikhHamad et al., 2001) (Zhang et al., 2002 could explain why clinical toxicity requires very high doses of these drugs over a very long period of time. Caffeine greatly potentiated the effect of acetaminophen, pointing to a pote...

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“…The genotoxic action of paracetamol in somatic cells has already been reported for mice bone marrow as chromosomal aberrations (CA) and sister chromatid exchange (SCE) (Giri et al, 1992). Treatment with paracetamol also induced SCE and CA and inhibits replicative DNA synthesis in mouse mammary tumor cell line (Hongslo et al, 1990). The significant increase in CA induced by paracetamol may be attributed to the fact that paracetamol can induce genotoxicity through DNA damage.…”

Section: Discussionmentioning

confidence: 98%

Effect of Zingiber Officinale on paracetamol-induced genotoxicity in male rats

Salah¹,

Abdouh²,

Booles³

et al. 2012

J. Med. Plants Res.

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The mutagenic effects of paracetamol (acetaminophen) in male rat using in vivo mutagenicity tests, chromosomal aberrations of somatic and germ cells, molecular assay and biochemical were studied. Paracetamol genotoxicity on normal divided cells has been reported. The data obtained showed that the ability of paracetamol to bind and interact with genetic material lead to changes in chromosomal behavior and structure during mitosis. The significant increase in chromosomal aberration, the changes in the number, position and intensity of bands, liver and renal damages induced by paracetamol may be attributed to the fact that paracetamol can induce genotoxicity through DNA damage. Paracetamol also stimulated AST and ALT activity, these stimulations indicated liver cell necrosis. Paracetamol-induced acute renal damage by the elevations in blood urea, uric acid and creatinine levels. Paracetamol showed abnormal values of protein profile in blood. The treatments with ginger presented hepatoprotective effect, also ginger can protect against oxidative kidneys tissue damage that reduced lipid peroxiation in liver and kidneys. The possible mechanism by which ginger exhibited significant protection against paracetamol-induced genotoxicity and hepatotoxicity may be due to its antioxidant effect. It may also be responsible for the hepatoprotective activity and attainment of normal frequencies of chromosomal aberration in ginger-treated rats. Thus, the present study indicated that the genotoxicity products at low concentration and for long time treatment showed the hazard of paracetamol addiction on human's life.

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Paracetamol inhibits replicative DNA synthesis and induces sister chromatid exchange and chromosomal aberrations by inhibition of ribonucleotide reductase

Cited by 53 publications

References 0 publications

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells

Toxicity of Acetaminophen, Salicylic Acid, and Caffeine for First-Passage Rat Renal Inner Medullary Collecting Duct Cells

Effect of Zingiber Officinale on paracetamol-induced genotoxicity in male rats

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