Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury

Abstract

Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopahological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described which is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examining the contribution of hepatic ATP-binding cassette (ABC) transporters as key contributors to DILI and how changes in their expression and function influence the development, severity and overall toxicity outcome.

Effects of food-derived oligopeptide iron chelates on liver injury and gut microbiota homeostasis in iron-deficiency anemia female rats: a pilot study

“…51,54,55 Moreover, ornithine is a precursor for synthesizing siderophores, and the increase of ornithine significantly increased siderophore production. 56 In the ID group, d- arginine and d- ornithine metabolism was significantly upregulated, perhaps leading to improvements in the efficiency of iron removal from the environment, which may have contributed to worsening ID in rats of the ID group. However, d- arginine and d- ornithine metabolism in the microbiota of the WPP-Fe and FeSO 4 groups was significantly decreased, revealing that these supplements have certain advantages for the ability of the rats to use the iron ingested.…”

Diagnóstico y manejo de la colestasis intrahepática en el embarazo

“…Los polimorfismos de nucleótido único que afectan al gen ABCB4 de la proteína MDR3 y al gen ABCB11 de la proteína transportadora de sales biliares también parecen ser importantes en la patogénesis de la CIE (12). Otras causas genéticas incluyen mutaciones del segundo par del cromosoma autosómico en la región p-23, una mutación del gen que codifica la enzima convertidora de angiotensina (12).…”

Special Section on Mechanistic and Translational Research on Transporters in Toxicology–Editorial

“…Together with metabolizing enzymes in the liver, these transporters play a key role in determining the concentrations of a drug and its metabolites in hepatocytes and contribute to DILI. In this special section, Dr. Jos e Manautou and his long-term collaborator, Dr. Carolina Ghanen from the University of Buenos Aires (Ghanem and Manautou, 2022), provide a comprehensive summary on the "Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury." As stated above, Dr. Manautou was the predoctoral mentor of Dr. Aleksunes, and is currently the Boehringer-Ingelheim Pharmaceuticals, Inc. chair in mechanistic toxicology and department head of pharmaceutical sciences and professor of toxicology at the University of Connecticut.…”