A metabolic profiling analysis of the nephrotoxicity of acyclovir in rats using ultra performance liquid
Wenmin Xing1, Lili Gu2, Xinyue Zhang3
1Zhejiang Provincial Key Lab of Geriatrics and Geriatrics Institute of Zhejiang Province, Zhejiang Hospital, Hangzhou 310013, China.
Abstract:
Acyclovir (ACV) exposure is a common cause of acute kidney injury (AKI). The toxicity mechanism of ACV has always been a matter of debate. The present study investigated into the time-effect relationship and dose-effect relationship of ACV-induced nephrotoxicity in rats using metabonomics. Twenty-four rats were randomly divided into four groups: a 0.9% NaCl solution group, and 100, 300, and 600mg/kg ACV-treated groups; the ACV or vehicle solution was administered with a single intravenous injection. Urine was collected at different time periods (12h before administration, and 0-6h, 7-12h, and 13-24h after administration). Routine urinalysis was conducted by a urine automatic analyzer. Renal markers, including urine urea nitrogen, urine creatinine, and urinary N-acetyl-β-d-glucosaminidase (NAG) activity, were determined using established protocols. Urinary metabolites were evaluated using ultra performance liquid chromatography/mass spectrometry (UPLC/MS). In the ACV-treated rats, increased levels of protein (PRO), occult blood (BLD), white blood cell (WBC), and NAG activity in urine were observed, while the urine creatinine and urea nitrogen levels showed a decrease compared with the control. Moreover, urine metabolites significantly changed after the treatment with ACV, and all the effects induced by ACV were dose-time dependent. Finally, 4 metabolites (guanine, 4-guanidinobutyric acid, creatinine, and urea) were identified, which can be used for further research on the mechanism of ACV-induced nephrotoxicity.
Insights
Acyclovir (ACV) exposure causes acute kidney injury (AKI) through dose- and time-dependent effects on rat kidneys. Metabonomics identified key urinary metabolites like guanine and creatinine, offering insights into ACV nephrotoxicity mechanisms.
Area of Science:
- Nephrology
- Toxicology
- Metabonomics
Background:
- Acyclovir (ACV) is a common cause of acute kidney injury (AKI).
- The precise mechanism of ACV-induced nephrotoxicity remains debated.
- Understanding the dose- and time-dependent effects is crucial for managing ACV toxicity.
Purpose of the Study:
- To investigate the time- and dose-dependent relationship of ACV-induced nephrotoxicity in rats.
- To identify urinary biomarkers indicative of ACV kidney injury using metabonomics.
- To elucidate the underlying mechanisms of ACV nephrotoxicity.
Main Methods:
- Rats were administered varying doses of ACV (100, 300, 600 mg/kg) or saline intravenously.
- Urine was collected at multiple time points post-administration for analysis.
- Routine urinalysis, renal marker assays, and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) based metabonomics were performed.
Main Results:
- ACV treatment led to increased urinary protein, occult blood, white blood cells, and N-acetyl-β-d-glucosaminidase (NAG) activity.
- Decreased urinary creatinine and urea nitrogen levels were observed in ACV-treated rats.
- Significant alterations in urinary metabolites were detected, showing clear dose- and time-dependent patterns.
Conclusions:
- ACV-induced nephrotoxicity in rats is demonstrably dose- and time-dependent.
- Four key urinary metabolites (guanine, 4-guanidinobutyric acid, creatinine, urea) were identified as potential biomarkers.
- These findings provide a foundation for further research into ACV nephrotoxicity mechanisms.
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