Developing urinary pyrrole–amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human

Lin Zhu, Chunyuan Zhang, Wei Zhang, Qingsu Xia, Jiang Ma, Xin He, Yisheng He, Peter P. Fu, Wei Jia, Yuzheng Zhuge*, Ge Lin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Pyrrolizidine alkaloids (PAs) have been found in over 6000 plants worldwide and represent the most common hepatotoxic phytotoxins. Currently, a definitive diagnostic method for PA-induced liver injury (PA-ILI) is lacking. In the present study, using a newly developed analytical method, we identified four pyrrole-amino acid adducts (PAAAs), namely pyrrole-7-cysteine, pyrrole-9-cysteine, pyrrole-9-histidine, and pyrrole-7-acetylcysteine, which are generated from reactive pyrrolic metabolites of PAs, in the urine of PA-treated male Sprague Dawley rats and PA-ILI patients. The elimination profiles, abundance, and persistence of PAAAs were systematically investigated first in PA-treated rat models via oral administration of retrorsine at a single dose of 40 mg/kg and multiple doses of 5 mg/kg/day for 14 consecutive days, confirming that these urinary excreted PAAAs were derived specifically from PA exposure. Moreover, we determined that these PAAAs were detected in ~ 82% (129/158) of urine samples collected from ~ 91% (58/64) of PA-ILI patients with pyrrole-7-cysteine and pyrrole-9-histidine detectable in urine samples collected at 3 months or longer times after hospital admission, indicating adequate persistence time for use as a clinical test. As direct evidence of PA exposure, we propose that PAAAs can be used as a biomarker of PA exposure and the measurement of urinary PAAAs could be used as a non-invasive test assisting the definitive diagnosis of PA-ILI in patients.

Original languageEnglish
Pages (from-to)3191-3204
Number of pages14
JournalArchives of Toxicology
Volume95
Issue number10
DOIs
Publication statusPublished - Oct 2021

Scopus Subject Areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

User-Defined Keywords

  • Biomarker
  • Hepatotoxicity
  • Non-invasive
  • Pyrrole-amino acid adducts
  • Pyrrolizidine alkaloids-induced liver injury

Fingerprint

Dive into the research topics of 'Developing urinary pyrrole–amino acid adducts as non-invasive biomarkers for identifying pyrrolizidine alkaloids-induced liver injury in human'. Together they form a unique fingerprint.

Cite this