Molecular mechanisms underlying chemical liver injury

Abstract

<jats:p>The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.</jats:p>

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

“…This can lead to chemical, and finally, functional modifications to cellular macromolecules, ultimately impairing cellular homeostasis (Han et al 2006). Oxidative stress-mediated drug hepatotoxicity is well known (Gu and Manautou 2012). The antitripanocide BZL has been shown to cause oxidative stress in rodent liver (Pedrosa et al 2001; Rendon 2014; Dias Novaes et al 2015).…”

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

“…Long noncoding RNAs can also bind microRNAs (miRNAs) (9,26,27), regulate alternative splicing (28), or pair with mRNAs via Alu repeats (29). Thus, long ncRNAs constitute a rich regulatory layer that can shape gene expression by diverse mechanisms.Mammalian liver plays a critical role in the metabolism of (30)(31)(32). The expression of genes that control liver metabolism and other functions can be dramatically altered by diverse stimuli, making the liver an ideal model for studies of condition-specific gene regulation and for investigation of ncRNAs that may contribute to these processes.…”

Xenobiotics and autoimmunity: does acetaminophen cause primary biliary cirrhosis?

“…The pathogenesis of most drug-induced liver injuries is initiated by the metabolic conversion of xenobiotics into reactive intermediate species, such as electrophilic compounds or free radicals, that can potentially alter the structure and function of cellular macromolecules to form neo-antigens. Furthermore, reactive intermediate species could lead to oxidative stress, deregulation of cell signaling pathways, the dysfunction of biomolecules, organelle malfunction, and eventual cell death [50]. Although it is not clear how xenobiotics or the modified cellular proteins initiate autoimmunity in PBC, analysis of serum samples from subjects with acute liver failure indicate that a severe liver oxidant injury can lead to AMA production [51].…”