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Genetics Biomarkers Of Hepatotoxicity

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During the last two decades Genome wide association studies (GWAS) have been carried out to investigate the relationship between genetic polymorphisms and DILI. The studies have focused on drugs that are very widely prescribed or newly licensed. Human leukocyte antigen (HLA) genome has been recognised a risk factor for DILI, even with some drugs where immune-related toxicity was unknown before.

However, even if GWAS can determine genetic causes of susceptibility to DILI, it cannot not yet explain the mechanism by which the injury is caused or identify patients at danger.Genomics biomarkers of hepatotoxicity Toxicogenomics, the use of genomics to detect patterns of changes in mRNA transcripts, for identification of DILI biomarkers, has gained momentum during the last decade. Microarray analysis of the rodent liver are usually used to find distinctive gene expression profiles as biomarkers and to reveal the molecular mechanism of DILI drugs. The gene expression profiles are used to generate gene expression signatures connected to drugs that cause DILI.These biomarkers that need liver biopsy for checking DILI progression in patients are inadequate in the clinical situation and genomics biomarkers from a far less invasive source, such as the blood, have been trialled in preclinical animals and humans.Interestingly, applying blood transcriptomic signatures, generated from rodents, to human blood enabled differentiation of APAP overdose patients from healthy controls. This study indicated that alterations in genes involved in an inflammatory response were the best discriminators between subtoxic/nontoxic and toxic exposure to APAP. In another study, a downregulation of mitochondrial genes involved complex I of the oxidative phosphorylation pathways was noted in blood from humans after APAP exposure consistent with earlier rat studies. In another study a more comprehensive approach was employed to demonstrate that transcriptomic signatures extracted from blood can predict liver injury caused by a wide variety of hepatotoxicants.In recent years, next-generation sequencing (NGS) technologies have allowed inexpensive effective sequencing of whole static genomes and dynamic transcriptomes and accurate quantification of gene expression including transcripts that have not been sequenced before.

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At the start, the comparability of NGS to microarray platforms in terms of gene expression and biological variability in a real-life toxicological study design needed to be assessed. The evaluation performed by the MicroArray Quality Control (MAQC) group showed that from the NGS platform and microarrays, consistent biological interpretation was generated.Converting these short sequences of NGS data to genomic biomarkers involves handling of large volumes of sequence data and bioinformatics tools are used to ensure sequence quality, perform sequence alignment to the appropriate genome and/ortranscriptome, and deliver a biological interpretation from the datasets.In recent years NGS has provided an increasingly comprehensive understanding of complex transcriptomes, at a cost and time effectiveness similar to that of microarrays. It is expected that NGS technologies will greatly contribute in detecting new DILI biomarkers.Proteomics biomarkers of hepatotoxicityIn order to find novel protein biomarkers proteomics assesses the differential protein expression between groups. Studies involve a separation step that can be ether gel-based or gel free and tandem mass spectrometry.

Biomarkers that have been identified by proteomics include biomarkers of acute kidney injury (AKI). There are as well reports showing potential classes of protein biomarkers of hepatoxicity such as the cytokines, whose production may be associated to an initial toxic injury that activates the biggest source of cytokine in the liver, the Kupffer cells.Hepatic response to different xenobiotics (including acetaminophen and PPAR ligands) are facilitated by cytokines. However, since the increase of cytokines is transitory and declines over time, it is necessary to decide a timeframe over which they should be studied after dosing (Lacour et al., 2005). ). IL-1 is a pro-inflammatory cytokine that has been proposedto be a biomarker for liver toxicity (Akbay et al.,1999; Lacour et al., 2005) and its activation can in turn produce the activation of other processes that lead to generalized hepatic damage.In response to a toxic reaction the cellular stress response pathways are also activated. Proteomic biomarkers linked to cellular stress response or toxicity pathways are summarised by Amacher (2010). Potential biomarkers belonging to this group include the annexin family of proteins that act as Ca2+ sensors and promote plasma membrane repair (Draeger et al., 2011), and those involved in anabolic functions, catabolic functions and drug metabolism (Fella et al., 2005).

Other potential biomarkers reported in a study of chemically induced hepatocarcinogenesis are, carbonic anhydrase III, aflatoxin B1 aldehyde reductase, and GST-P (Fella et al., 2005). In addition, other markers of hepatocellular stress are keratins, responsible for cell structure and integrity and HMGB-1, a marker of inflammation as well as necrosis but not apoptosis (Scaffidi et al., 2002).Several alternative serum biomarkers for assessing liver injury have been researched and it is too early to know if they will be more selective than ALT and AST. Some of them are: glutamate dehydrogenase (GLDH), paraoxonase1 (PON1), purine nucleoside phosphorylase (PNP), serum F protein, malate dehydrogenase (MDH), sorbitol dehydrogenase, glutathione-S-transferase alpha (GSTα), and arginase I (Ozer et al., 2008; Schomaker et al., 2013). GLDH activity is more liver-specific than ALT and AST. GLDH and MDH are linked to elevated ALT in an extensive range of liver injuries (Schomaker et al., 2013). However, MDH is used as well as a biomarker for cardiac disease and hypertension (Zieve et al., 1985). PNP, an enzyme involved in purine metabolism, has not been confirmed as a valid biomarker for human liver injury. PNO1 in serum decreases, unike other serum biomarkers in serum after liver injury, and it has been shown to be higher in African Americans compared with Caucasians (Schomaker et al.,2013). Serum F protein is a sensitive and specific marker of liver damage strongly correlated to histopathology in humans (Foster et al., 1989).


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