Genotoxic and mutagenic potential of 7-methylxanthine: an investigational drug molecule for the treatment of myopia

Abstract

7-Methylxanthine (7-MX, CAS No. 552-62-5, purity 99.46%) is the first orally administered drug candidate, which showed anti-myopic activity in different pre-clinical studies. In the present study, we investigated the in-vivo genotoxic and mutagenic toxicity of 7-MX in Wistar rats using comet/single-cell gel electrophoresis, chromosomal aberration and micronucleus assays after oral administration. For the single-dose study (72 h), two doses of 7-MX 300 and 2000 mg/kg body weight were selected. For a repeated dose 28 d study, three doses (250, 500, and 1000 mg/kg) of 7-MX were selected. The doses were administered via oral gavage in the suspension form. Blood and major vital organs such as bone marrow, lung and liver were used to perform comet/single cell gel electrophoresis, chromosomal aberration, and micronucleus assays. The in-vitro Ames test was performed on TA98 and TA100 strains. In the chromosomal aberration study, a non-significant increase in deformities such as stickiness, ring chromosome, and endoreduplication was observed in bone marrow cells of 7-MX treated groups. These chromosomal alterations were observed upon treatment with doses of 2000 mg/kg single dose for 72 h and 1000 mg/kg repeated dose for 28 d. At a dose of 500 mg/kg, DNA damage in terms of tail length, tail moment, % tail DNA and the olive tail moment was also found to be non-significant in 7-MX treated groups. The Ames test showed the non-mutagenic nature of 7-MX in both strains of TA98 and TA100 of Salmonella typhimurium with or without metabolic activation. Thus, the present work is interesting in view of the non- genotoxicity and non-mutagenicity of repeated doses of 7-MX.

Keywords:

• 7-Methyl xanthine (7-MX
• CAS No. 552-62-5
• purity 99%)
• Wistar rats
• comet assay
• genotoxicity
• Ames test
• chromosomal aberration
• myopia

Acknowledgements

The authors are grateful to the Department of Science & Technology, New Delhi for financial assistance to the Department of Pharmaceutical Sciences, under the DST-FIST scheme (sanction no. SR/FST/LSI-657/2016). Authors are also grateful to University Grant Commission (UGC), New Delhi to provide grants in aid to Guru Nanak Dev University, Amritsar under component 4.0 of RUSA 2.0 scheme to establish Center for Basic and Translational Research in Health Sciences (CBTRHS). The authors are also grateful to the All India Council for Technical Education (AICTE) for providing financial support [Sanction no. 9–47/1DC/MODROB/Policy-1/2019–20]. The authors are also thankful to V.B. Medicare Pvt. Ltd. Hosur, Bangalore for providing 7-MX.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.