A metabolomic perspective of griseofulvin-induced liver injury in mice.

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.

• Authors: Ke Liu, Jiong Yan, Madhav Sachar, Xinju Zhang, Ming Guan, Wen Xie, Xiaochao Ma
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 98 Issue 3 Pg. 493-501 (Dec 01 2015) ISSN: 1873-2968 [Electronic] England
• PMID: 26343413 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antifungal Agents
• Griseofulvin
• Glutathione
• Glutathione Disulfide

Topics

• Animals
• Antifungal Agents (toxicity)
• Glutathione (metabolism)
• Glutathione Disulfide (metabolism)
• Griseofulvin (toxicity)
• Liver (drug effects, metabolism)
• Male
• Metabolomics
• Mice