Xenobiotic-induced Liver Injury Research Articles

Role of baicalin as a potential therapeutic agent in hepatobiliary and gastrointestinal disorders: A review.

Baicalin is a natural bioactive compound derived from Scutellaria baicalensis, which is extensively used in traditional Chinese medicine. A literature survey demonstrated the broad spectrum of health benefits of baicalin such as antioxidant, anticancer, anti-inflammatory, antimicrobial, cardio-protective, hepatoprotective, renal protective, and neuroprotective properties. Baicalin is hydrolyzed to its metabolite baicalein by the action of gut microbiota, which is further reconverted to baicalin via phase 2 metabolism in the liver. Many studies have suggested that baicalin exhibits therapeutic potential against several types of hepatic disorders including hepatic fibrosis, xenobiotic-induced liver injury, fatty liver disease, viral hepatitis, cholestasis, ulcerative colitis, hepatocellular and colorectal cancer. During in vitro and in vivo examinations, it has been observed that baicalin showed a protective role against liver and gut-associated abnormalities by modifying several signaling pathways such as nuclear factor-kappa B, transforming growth factor beta 1/SMAD3, sirtuin 1, p38/mitogen-activated protein kinase/Janus kinase, and calcium/calmodulin-dependent protein kinase kinaseβ/adenosine monophosphate-activated protein kinase/acetyl-coenzyme A carboxylase pathways. Furthermore, baicalin also regulates the expression of fibrotic genes such as smooth muscle actin, connective tissue growth factor, β-catenin, and inflammatory cytokines such as interferon gamma, interleukin-6 (IL-6), tumor necrosis factor-alpha, and IL-1β, and attenuates the production of apoptotic proteins such as caspase-3, caspase-9 and B-cell lymphoma 2. However, due to its low solubility and poor bioavailability, widespread therapeutic applications of baicalin still remain a challenge. This review summarized the hepatic and gastrointestinal protective attributes of baicalin with an emphasis on the molecular mechanisms that regulate the interaction of baicalin with the gut microbiota.

Vitamins A and D fail to protect against tuberculosis-drug-induced liver injury: A post hoc analysis of a previous randomized controlled trial

ObjectivesVitamins A and D provided protection from xenobiotic-induced liver injury in previous animal studies. We conducted a post hoc analysis of our previous randomized controlled trial to investigate the effects of vitamin A and D supplementation on tuberculosis-drug-induced liver injury. MethodsThe trial was conducted in a hospital in Qingdao, China, from October 2012 to March, 2015. The control group received only tuberculosis treatment. The vitamin A, vitamin D, and vitamins A & D groups received, respectively, additional supplementation of 2000 IU/d vitamin A, 400 IU/d vitamin D, and a combination of 2000 IU/d vitamin A and 400 IU/d vitamin D. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, γ-glutamyltransferase, and cholinesterase were monitored throughout the treatment. Liver injury was defined as ALT or AST three times higher than the upper limit of normal, which was defined for AST, ALT, alkaline phosphatase, γ-glutamyltransferase, and cholinesterase, respectively, as 40 U/L, 40 U/L, 150 U/L, 40 U/L, and 10 500 U/L. ResultsAmong the 753 participants, 11% exhibited liver injury. No significant effect of vitamin A or D supplementation was observed on the incidence of liver injury or on elevated liver indices including ALT, AST, alkaline phosphatase, γ-glutamyltransferase, and cholinesterase. The interaction between vitamin A and D supplementation was not significant. ConclusionsVitamin A and D supplementation did not protect against tuberculosis-drug-induced liver injury. Future work should evaluate the effects of higher dosages of vitamins A and D and the effects of different genotypes for vitamin A and D metabolic enzymes or receptors.

Potential Beneficial Actions of Fucoidan in Brain and Liver Injury, Disease, and Intoxication-Potential Implication of Sirtuins.

Increased interest in natural antioxidants has brought to light the fucoidans (sulfated polysaccharides present in brown marine algae) as highly valued nutrients as well as effective and safe therapeutics against several diseases. Based on their satisfactory in vitro antioxidant potency, researchers have identified this molecule as an efficient remedy for neuropathological as well as metabolic disorders. Some of this therapeutic activity is accomplished by upregulation of cytoprotective molecular pathways capable of restoring the enzymatic antioxidant activity and normal mitochondrial functions. Sirtuin-3 has been discovered as a key player for achieving the neuroprotective role of fucoidan by managing these pathways, whose ultimate goal is retrieving the entirety of the antioxidant response and preventing apoptosis of neurons, thereby averting neurodegeneration and brain injuries. Another pathway whereby fucoidan exerts neuroprotective capabilities is by interactions with P-selectin on endothelial cells, thereby preventing macrophages from entering the brain proper. Furthermore, beneficial influences of fucoidan have been established in hepatocytes after xenobiotic induced liver injury by decreasing transaminase leakage and autophagy as well as obtaining optimal levels of intracellular fiber, which ultimately prevents fibrosis. The hepatoprotective role of this marine polysaccharide also includes a sirtuin, namely sirtuin-1 overexpression, which alleviates obesity and insulin resistance through suppression of hyperglycemia, reducing inflammation and stimulation of enzymatic antioxidant response. While fucoidan is very effective in animal models for brain injury and neuronal degeneration, in general, it is accepted that fucoidan shows somewhat limited potency in liver. Thus far, it has been used in large doses for treatment of acute liver injuries. Thus, it appears that further optimization of fucoidan derivatives may establish enhanced versatility for treatments of various disorders, in addition to brain injury and disease.

Hepatic Stellate Cell-Derived Microvesicles Prevent Hepatocytes from Injury Induced by APAP/H2O2.

Hepatic stellate cells (HSCs), previously described for liver-specific mesenchymal stem cells (MSCs), appear to contribute to liver regeneration. Microvesicles (MVs) are nanoscale membrane fragments, which can regulate target cell function by transferring contents from their parent cells. The aim of this study was to investigate the effect of HSC-derived MVs on xenobiotic-induced liver injury. Rat and human hepatocytes, BRL-3A and HL-7702, were used to build hepatocytes injury models by n-acetyl-p-aminophenol n-(APAP) or H2O2 treatment. MVs were prepared from human and rat HSCs, LX-2, and HST-T6 and, respectively, added to injured BRL-3A and HL-7702 hepatocytes. MTT assay was utilized to determine cell proliferation. Cell apoptosis was analyzed by flow cytometry and hoechst33258 staining. Western blot was used for analyzing the expression of activated caspase-3. Liver injury indicators, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in culture medium were also assessed. Results showed that (1) HSC-MVs derived from LX-2 and HST-T6 were positive to CD90 and annexin V surface markers; (2) HSC-MVs dose-dependently improved the viability of hepatocytes in both injury models; (3) HSC-MVs dose-dependently inhibited the APAP/H2O2 induced hepatocytes apoptosis and activated caspase-3 expression and leakage of LDH, ALT, and AST. Our results demonstrate that HSC-derived MVs protect hepatocytes from toxicant-induced injury.

Biomarkers of drug-induced liver injury

Correspondence: Kai Wang Institute for Systems Biology 401 Terry Avenue North Seattle, Washington 98109, USA Tel +1 206 732 1336 Fax +1 206 732 1299 Email kwang@systemsbiology.org Abstract: The liver plays a central role in metabolizing xenobiotics; therefore, it is highly susceptible to toxicity from these chemicals. Certain drugs, when taken in overdose and sometimes even when used within therapeutic range, may cause injury to the organ. Druginduced liver injury is now not only a leading cause of acute liver failure in the US, but is also a leading reason for discontinuation of drugs in development and for regulatory actions against previously approved drugs. The current clinical biomarkers to detect and monitor drug-induced liver injury are inadequate in terms of sensitivity and/or specificity, prompting the need for more informative biomarkers. The development of high throughput proteomics, genomics, and metabolomics technologies has the potential to fulfill such demand. The discipline of systems toxicology may add to our understanding of perturbed xenobiotic networks, which may lead to network-specific surrogate markers and therapeutic means to stop or reverse xenobiotic-induced liver injury.

Detection of early signals of hepatotoxicity by gene expression profiling studies with cultures of metabolically competent human hepatocytes

Xenobiotic induced liver injury is a leading cause for drug withdrawal and toxicogenomics may help to identify molecular causes. Here we report studies with cultures of human hepatocytes to detect early responses of liver toxicity upon treatment with the hepatotoxin Aroclor 1254. We studied transcript abundance of 302 genes with biological functions in detoxification, cell proliferation, tumor development, stress response, signal transduction, apoptosis and cell cycle regulation. More than 40 genes were regulated by at least twofold change, the majority coding for xenobiotic defense. In the case of CYP monooxygenases induction of coded protein was confirmed by Western immunoblotting whereas catalytic activities were determined by assaying for testosterone hydroxylase activity. There was good agreement between gene and protein expression and enzyme activity of CYP monooxygenases. In conclusion, xenobiotic induced hepatotoxicity may arise via several mechanisms and gene expression profiling helps to pinpoint location and pathways perturbed by drugs and chemicals.

Macrophage responses in xenobiotic-induced liver injury and carcinogenesis of a marine flatfish

In North Sea flounder ( Platichthys flesus L.) toxipathic liver lesions and progression to malignant hepatocellular carcinomas associated with metabolic changes (G6PDH, BzALDH, CYP450, GST, P-gp related MXR) were observed. Our interest is now directed towards the response of macrophages in toxipathic liver lesions and towards altered hepatocellular foci and carcinomas. The activity of macrophages was monitored by acid phosphatase activity. Simultaneously, lysosomal integrity and DNA strand breaks (TUNEL assay) were measured as biomarkers of cell injury and death in serial sections. Our results indicate that macrophage response and activity are primarily reduced in flounder from more contaminated habitats. During carcinogenesis, macrophage immigration is stimulated but activity in extrafocal tissue is downregulated in areas close to carcinomas. Macrophage centers are obviously ignored and circumgrown by invading cancer cells. We presently investigate whether cancer cell-specific signals, such as interleukin 10, transforming growth factor β and prostaglandin E 2 which induce macrophage inactivation in mammals, play a role in arrest of immune response against invading cancer cells in lower vertebrates.

Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function

Xenobiotic-induced liver injury is a clinically important etiology of hepatic disease that, if not recognized, can lead to hepatic failure. In this article we discuss the mechanisms of xenobiotic-induced liver injury, various factors that can alter the risk and severity of injury, the clinical and laboratory manifestations of injury, and the methods used to detect the presence of injury and (or) functioning liver mass.

The differential effects of hepatotoxicants on the sulfation pathway in rats

This study characterized the effects of liver damage produced by a variety of hepatotoxicants on several components of the sulfation pathway in rats. Specifically, the concentration of cosubstrate, adenosine 3′-phosphate 5′-phosphosulfate (PAPS), and the hepatic capacity for PAPS synthesis were measured in livers of rats treated with carbon tetrachloride (CCl 4), 1,1-dichloroethylene (DCE), α-naphthylisothiocyanate (ANIT), aflatoxin B 1 (ATX), allyl alcohol (AA), bromobenzene (BB), cadmium chloride (Cd), or thioacetamide (TA). Liver damage was assessed by measuring serum sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALT) activities as well as by histopathological examination. Hepatic PAPS concentration was generally decreased as a result of treatment with hepatotoxicants (35–80% of control), although BB, AA, and ANIT were without effect. Maximal hepatic capacity for PAPS synthesis, determined as the activities of PAPS synthetic enzymes, ATP sulfurylase, and APS kinase, was selectively decreased by the hepatotoxicants. ATP sulfurylase activity was decreased by Cd and TA (55 and 62% of control, respectively), whereas APS kinase activity was decreased by Cd, TA, BB, and DCE (60–77% of control, respectively). In addition, phenol sulfotransferase (PST) activity was measured toward 1- and 2-naphthol in order to determine whether apparent changes in PST activity in damaged livers are substrate-dependent. Treatment with hepatotoxicants generally decreased 1-naphthol-directed PST activity but not PST activity directed toward 2-naphthol. In conclusion, (1) not all xenobiotic-induced liver injury results in decreased hepatic PAPS concentration, (2) some hepatotoxicants decrease PAPS concentration by a mechanism other than decreased cosubstrate synthesis, and (3) the effect of hepatotoxicants on PST activity is dependent upon the choice of substrate used in the enzymatic assay.