Evaluation genotoxicity of acetylnerolin based on quantitative structure-activity relationship model and in vitro tests
10.3867/j.issn.1000-3002.2020.03.002
- VernacularTitle:基于构效关系模型和体外实验的acetylnerolin遗传毒性评价
- Author:
Yin-Nan WU
1
;
Wan TANG
;
Jing YIN
;
Yang LIU
;
Yu-Xin WANG
;
Yi-Hong LU
Author Information
1. 徐州医科大学药物分析教研室
- Keywords:
chromosomal aberration;
quantitative structure-activity relationship;
naproxen
- From:
Chinese Journal of Pharmacology and Toxicology
2020;34(3):171-178
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE To evaluate the genotoxicity of naproxen (NPX) impurities acetylnerolin (Ace). METHODS The genotoxicity of Ace was predicted by ADMET, Derek and Sarah with the quanti?tative structure-activity relationship (QSAR). The chromosomal aberration and bacterial reverse-muta?tion (Ames) tests were performed to verify the above results. In chromosomal aberration tests, CHL cells were incubated with Ace 10, 20 and 40 mg · L-1 for 4 h in the presence or absence of metabolic activation system solution (S9 mix). Methyl methane sulfonate (MMS) 20 mL · L-1 without S9 mix and cyclophosphamide (CP) 12 mg · L-1 with S9 mix served as positive control. The number of chromo?somes in each aberrant metaphase (including fissure, exchange, ring, break and polyploid) was counted and recorded, when the distortion rate less than 5％was considered negative and more than 10％was considered positive. In Ames test, the potential mutagenicity was evaluated using five strains of S. typhimurium ( TA97,TA98,TA100,TA102 and TA1535). They were treated with Ace 5, 25, 125 and 625μg per plate with or without S9 mix and incubated for 48-72 h. When without S9 mix, Dexon 50μg per plate served as positive control for TA97 and TA98, MMS 2.0μL per plate served as positive control for TA100 and TA102, and sodium azide 1.5μg per plate served as positive control for TA1535. When with S9 mix, 2-AF 100 μg per plate served as positive control for TA97, TA98 and TA100, 1, 8-dihydroxyanthraquinone (100μg per plate) served as positive control for TA102 and CP 50μg per plate served as positive control for TA1525. When the number of colonies was at least two-fold that of the negative control, the compound was considered mutagenic. RESULTS Although the Derek and Sarah software predicted that the NPX impurities were not genotoxic, ADMET data showed that Ace could induce chromosomal aberrations. The distortion rate of Ace 40 mg · L-1 was greater than 5％, but less than 10％. The distortion rate of Ace was less than 5％when<20 mg·L-1. Consistent with the results of ADMET, Ace might induce chromosomal aberrations. Ames test results showed that Ace did not signifi?cantly increase the number of bacteria (5-625μg per plate) compared with the negative control. Contrary to the ADMET results, Ace had no mutagenicity. CONCLUSION Ace has potential chromosomal muta?genicity. For life-long usage of NPX, the content of Ace should be reduced from 0.15％of conventional impurities to 0.015％.
