A metabolomic perspective of griseofulvin-induced liver injury in mice

Biochemical Pharmacology
Ke LiuXiaochao Ma

Abstract

Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans.

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Citations

Jul 21, 2016·Chemical Research in Toxicology·Madhav SacharXiaochao Ma
Jun 14, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yi-Kun WangFei Li
Apr 6, 2017·EMBO Molecular Medicine·Halesha D BasavarajappaTimothy W Corson
Jul 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sardar Pasha Sheik Pran BabuTimothy W Corson
Aug 2, 2017·Current Pharmacology Reports·Pengcheng WangXiaochao Ma
Aug 8, 2020·Frontiers in Pharmacology·Trupti Shetty, Timothy W Corson
Nov 24, 2020·Journal of the American Veterinary Medical Association·Brittany C KunzKarl E Anderson
Aug 13, 2021·The Science of the Total Environment·Lilong JiangZongwei Cai

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