Evaluation of the nephrotoxicity and safety of low-dose aristolochic acid, extending to the use of Xixin (Asurum), by determination of methylglyoxal and D-lactate

Chia En Lin, Po Yeh Lin, Wen Chi Yang, Yu Shen Huang, Tzu Yao Lin, Chien‐Ming M. Chen, Hung Shing Chen, Jen Ai Lee, Shih Ming Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Ethnopharmacological relevance: Most Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin (Asarum spp.). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and D-lactate are regarded as biomarkers for nephrotoxicity. Aim of the study: The use of Xixin (Asarum spp.) is essential and controversial. This study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and D-lactate after withdrawal of low-dose AA in a chronic mouse model. Materials and methods: C3H/He mice in the AA group (n = 24/group) were given ad libitum access to distilled water containing 3 μg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson's trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary D-lactate were determined by column-switching HPLC. Results: After AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4 ± 48.3 μg/L) to 84 (600.2 ± 99.9 μg/L), and peaked on day 70 (878.3 ± 171.8 μg/L; p < 0.05); TIHS and fibrosis exhibited similar patterns. Urinary methylglyoxal was high on day 56 (3.522 ± 1.061 μg), declined by day 70 (1.583 ± 0.437 μg) and increased by day 84 (2.390 ± 0.130 μg). Moreover, urinary D-lactate was elevated on day 56 (82.10 ± 18.80 μg) and higher from day 70 (201.10 ± 90.82 μg) to 84 (193.28 ± 61.32 μg). Conclusions: Methylglyoxal is induced after AA-induced tubulointerstitial injury, so methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and helps to repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).

Original languageEnglish
Article number113945
JournalJournal of Ethnopharmacology
Volume272
DOIs
Publication statusPublished - May 23 2021

Keywords

  • Aristolochic acid (AA)
  • D-lactate
  • Fibrosis
  • Methylglyoxal
  • Nephrotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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