Pyrrole-protein adducts - A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity

Jiang Ma; Qingsu Xia; Peter P Fu; Ge Lin

doi:10.1016/j.jfda.2018.05.005

Pyrrole-protein adducts - A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity

J Food Drug Anal. 2018 Jul;26(3):965-972. doi: 10.1016/j.jfda.2018.05.005. Epub 2018 Jun 14.

Authors

Jiang Ma^{1

2}, Qingsu Xia³, Peter P Fu³, Ge Lin^{1

2}

Affiliations

¹ School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
² Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between the Chinese University of Hong Kong and Shanghai Institute of Materia Medica, China Academy of Sciences, China.
³ National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, 72079, USA.

Abstract

Pyrrolizidine alkaloids (PAs) are phytotoxins identified in over 6000 plant species worldwide. Approximately 600 toxic PAs and PA N-oxides have been identified in about 3% flowering plants. PAs can cause toxicities in different organs particularly in the liver. The metabolic activation of PAs is catalyzed by hepatic cytochrome P450 and generates reactive pyrrolic metabolites that bind to cellular proteins to form pyrrole-protein adducts leading to PA-induced hepatotoxicity. The mechanisms that pyrrole-protein adducts induce toxicities have not been fully characterized. Methods for qualitative and quantitative detection of pyrrole-protein adducts have been developed and applied for the clinical diagnosis of PA exposure and PA-induced liver injury. This mini-review addresses the mechanisms of PA-induced hepatotoxicity mediated by pyrrole-protein adducts, the analytical methods for the detection of pyrrole-protein adducts, and the development of pyrrole-protein adducts as the mechanism-based biomarker of PA exposure and PA-induced hepatotoxicity.

Keywords: Clinical diagnosis; Covalent binding; Mechanism-based biomarker; Pyrrole-protein adducts; Pyrrolizidine alkaloids; Target protein.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Biomarkers / chemistry
Biomarkers / metabolism
Chemical and Drug Induced Liver Injury / etiology*
Humans
Liver / drug effects
Liver / metabolism
Proteins / chemistry*
Proteins / metabolism
Pyrroles / chemistry*
Pyrroles / metabolism
Pyrrolizidine Alkaloids / chemistry
Pyrrolizidine Alkaloids / metabolism
Pyrrolizidine Alkaloids / toxicity*

Substances

Biomarkers
Proteins
Pyrroles
Pyrrolizidine Alkaloids

Grants and funding

The funding supported by Research Grants Council of Hong Kong (Ref. No.: 14110714 and 14111816), The Chinese University of Hong Kong (CUHK) for the Direct Grants (Ref. No.: 4054376), and School of Biomedical Sciences–Seed Fund for Joint Establishments are acknowledged.