Abstract
Realgar has been used as a type of mineral drug that contains arsenic for thousands of years. Previous studies have shown that Realgar-induced acute kidney injury is associated with abnormal metabolism, but the underlying mechanism is poorly understood. The aim of this study is to investigate the metabolic changes in serum and kidney tissues of mice exposed to Realgar by using a metabolomic approach and explore the molecular mechanisms of acute kidney injury induced by Realgar. Forty mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After 1 week, the body weight and kidney weight of the mice were measured. The serum and kidney samples were used for LC-MS spectroscopic metabolic profiling. Principal component analysis (PCA), correlation analysis, and pathway analysis were used to detect the nephrotoxic effects of Realgar. Body weight decreased significantly in the 2.0 g/kg group, and the kidney weight index also showed a dose-dependent increase in Realgar. The PCA score plot showed the serum and kidney tissue metabolic profile of mice exposed to 2.0 g/kg Realgar separated from the control group, while the lower-doses of 0.5 g/kg and 1.0 g/kg Realgar shown a similar view to the Control group. Thirty-three metabolites and seventeen metabolites were screened and identified in the serum and kidney of mice in a dose-dependent manner. respectively. Correlation analysis showed a strong correlation among these metabolites. Amino acid metabolism, lipid metabolism, glutathione metabolism, and purine metabolism pathways were found to be mainly associated with Realgar nephrotoxicity. This work illustrated the metabolic alterations in Realgar-induced nephrotoxic mice through a metabolomic approach.
Highlights
Arsenic has long been known as a toxic compound and environmental carcinogen, which exposure causes oxidative stress, apoptosis, chromosomal abnormalities, and DNA damage (Zhou and Xi, 2018; Palma-Lara et al, 2020)
Our previous work revealed that Realgar can cause acute kidney injury and it is mainly related to the metabolic pathways (Zhang et al, 2021)
A significant reduction in body weight were observed in the 2.0 g/kg Realgar group, which may be due to persistent non-remission of Realgar-acute kidney injury, increased toxin levels, and inadequate intake of ingested nutrients
Summary
Arsenic has long been known as a toxic compound and environmental carcinogen, which exposure causes oxidative stress, apoptosis, chromosomal abnormalities, and DNA damage (Zhou and Xi, 2018; Palma-Lara et al, 2020). As an arseniccontaining compound, has shown good remission in the treatment of acute promyelocytic leukemia (APL) (Min et al, 2020). Arsenic trioxide shows great toxic effects and causes serious adverse reactions especially in the case of long-term use (Wang et al, 2020). Realgar has similar efficacy to arsenic trioxide in the treatment of APL and has fewer side effects (Wu et al, 2011). Arsenic contained in Realgar is still a potentially toxic substance. Realgar and its compounds can cause adverse reactions or chronic arsenic poisoning when used chronically, in excess, and irregularly (Yi et al, 2018; Zheng et al, 2019). The metabolism of arsenic in Realgar-induced toxicity plays a leading role.
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