Comparative mutagenic and genotoxic effects of three propionic acid derivatives ibuprofen, ketoprofen and naproxen

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Abstract

The mutagenicity of three propionic acid derivatives, namely ibuprofen, ketoprofen and naproxen, was tested in the Ames mutagenicity assay (in strains TA97a, TA100 and TA102) and in vivo genotoxicity was tested by sister chromatid exchange (SCE) in bone marrow cells of mice. These are the anti-inflammatory drugs frequently used in different parts of the world. Mutagenicity results showed no mutagenic effects in strains TA97a, TA100 and TA102 for all three drugs. Results of in vivo SCE assays indicate that these three drugs are weakly genoxic in bone marrow cells of mice. This is the first report of the Ames mutagenicity assay for ketoprofen and in vivo SCE assay for three drugs.

Introduction

Ibuprofen (IB), ketoprofen (KP) and naproxen (NP) are three propionic acid derivatives commonly used as anti-inflammatory drugs (see Fig. 1). IB is a non-steroidal anti-inflammatory drug used in painful and inflammatory conditions [1]. This drug was the first member of the group that came into general use. It has been approved for sale without prescription in the United States [2]. IB is used in rheumatoid arthritis, osteoarthritis, for relief of mild to moderate pain, primary dysmenorrhoea and reduction of fever [3].

Ketoprofen has analgesic and antipyretic properties similar to other non-steroidal anti-inflammatory drugs. It is a very strong analgesic which is used in musculoskeletal and joint disorders, such as ankylosing spondylitis, osteoarthritis, acute gout, and in mild to moderate pain, such as dysmenorrhoea or postoperative pain [3]. But, because of the severe skin reactions and the possibility of cross-reaction this drug is not in very common use.

Naproxen is also a non-steroidal anti-inflammatory drug which has a long half-life [2]. It is generally used for the treatment of primary dysmenorrhoea, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, acute gout and juvenile arthritis [3].

Acute dose of these non-steroidal anti-inflammatory drugs increases the frequency of pseudoporphyria [4]. IB has been reported to induced gastrointestinal bleeding, meningitis, lymphopenia and hepatotoxicity 5, 6, 7, 8, 9. It inhibits the synthesis of prostacyclin and prostaglandin of type E 10, 11. Acute ingestion of IB results in nephritis, proteinuria, renal failure, adult respiratory distress syndrome and metabolic acidosis 12, 13. KP is found to cause severe skin reaction, hypersentivity, myasthenia gravis and photosentivity [14]. It also decreases the metabolic activity of aged male rats [15]. NP is reported to induce renal papillary necrosis and a disproportionate increase in renal excretion 16, 17. Like other anti-inflammatory drugs, acute renal disfunction is observed in all the cases of NP overdose [18]. IB and NP are not mutagenic in the Ames Salmonella reversion test 19, 20.

Reports on the in vitro mutagenicity assays for these three drugs are very scarce. There is no report of in vivo SCE in mice for these drugs. We have been testing the in vitro and in vivo mutagenic and genotoxic effects of different environmental chemicals and drugs 21, 22, 23, 24, 25, 26. Because of the adverse toxic effects of these drugs in humans and in experimental animals, we recognise the need to extend the in vitro mutagenicity assay in Salmonella strains TA97a, TA100 and TA102 and the in vivo SCE assay in bone marrow cells of mice for these three drugs, namely IB, KP and NP.

Section snippets

Animals

Swiss albino male mice (Mus musculus), 10–12 weeks old, weighing 30 g and Charles River male rats of 150–175 g were obtained from the Division of Laboratory Animals, Central Drug Research Institute, Lucknow. They were kept 5 per cage with husk bedding, were fed standard rodent pellet diet (Gold Mohar, Lipton India Ltd., Chandigarh, India) and water ad libitum. The light cycle was 12:12 h light/dark. Room temperature and relative humidity conditions were 28±2°C and 60±5%, respectively. Mice were

Results and discussion

Summary of the results of mutagenic effects of IB, KP and NP tested on Salmonella strains TA97a, TA100 and TA102 are given in Table 1Table 2Table 3. The spontaneous reversion frequencies observed for all the strains were consistent with values reported by Maron and Ames [28]. Since, two independent experiments were carried out for mutagenicity assay so the mean value of two plates in each independent experiment has been presented in the tables. Statistical calculations were carried out with the

Acknowledgements

The authors are extremely grateful to the Division of Biometry and Statistics, Central Drug Research Institute for their help in statistical calculation of our data. Thanks are also due to Dr. K.A.I. Siddiqui, Scientist, Indian Institute of Chemical Biology, Calcutta for his comments and suggestions.

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