Single-Dose Toxicity Study on ML171, a Selective NOX1 Inhibitor, in Mice
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Published on: July 21, 2018
Se-Hyun Oh1,2, Ji-Sun Ahn1, Eun-Joo Oh1
1Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea.
Background:
ML171 is a potent nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor with isoform selectivity only for NOX1. This study is aimed at investigating the safety of ML171 after a single intraperitoneal (IP) injection in mice.
Methods:
The toxicity of a single dose of ML171 was evaluated in 6-week-old Institute of Cancer Research (ICR) mice in a good laboratory practice (GLP) laboratory. Twenty-five mice of each sex were assigned to five groups: negative control, vehicle control, and 125, 250, and 500 mg/kg of ML171. All mice were acclimatized for one week before beginning the study. Mice received an IP injection of ML171 or vehicle. The general condition and mortality of the animals were observed. The mice were sacrificed to evaluate histopathology 14 days after the administration of ML171 or vehicle.
Results:
Bodyweights were not significantly different in any group. Three males and one female died due to ML171 administration in the 500 mg/kg dose group. Autopsies of the surviving mice did not reveal any significant abnormalities after the injection of 125 mg/kg of ML171. However, the anterior lobe edge of the liver was thickened and adhesions between the liver and adjacent organs were observed in mice treated with 250 or 500 mg/kg of ML171. In addition, hypertrophy of centrilobular hepatocytes and inflammatory cell infiltration were observed after injection of 250 and 500 mg/kg of ML171.
Conclusion:
Our results indicate that the lethal IP injection dose of ML171 is 500 mg/kg for both males and females. Mortality were not observed for lower doses of ML171. The safe dose of single IP ML171 in ICR mice was 250 mg/kg or less. Further studies are needed to confirm the safety of ML171 in the human body.
Insights
The nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor ML171 showed a lethal dose of 500 mg/kg in mice. Doses of 250 mg/kg or less were determined to be safe for single intraperitoneal injection.
Area of Science:
- Pharmacology
- Toxicology
- Biochemistry
Background:
- ML171 is a selective inhibitor of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1).
- Understanding the safety profile of NOX inhibitors is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the safety and toxicity of ML171 following a single intraperitoneal (IP) injection in mice.
- To determine the maximum tolerated dose (MTD) and identify potential adverse effects of ML171.
Main Methods:
- A single IP injection toxicity study was conducted in 6-week-old ICR mice.
- Mice (n=25/sex/group) received doses of 0, 125, 250, or 500 mg/kg ML171.
- General condition, mortality, body weight, and histopathology were assessed 14 days post-injection.
Main Results:
- No significant body weight changes were observed across groups.
- Mortality occurred at the 500 mg/kg dose (3 males, 1 female).
- Hepatotoxicity, including liver lobe thickening, adhesions, hepatocyte hypertrophy, and inflammation, was observed at 250 and 500 mg/kg.
Conclusions:
- The lethal dose of ML171 via IP injection in mice is 500 mg/kg.
- A single IP dose of 250 mg/kg or less is considered safe in ICR mice.
- Further investigation is warranted to assess ML171 safety in humans.
