Role In Hepatotoxicity Research Articles

Phytochemical Investigation and GC-MS analysis of Tribulus terrestris L. cultivated in Iraq

Tribulus terrestris L.,Gokshur in Sanskt, is an annual herbaceous, little prostrate, silky from the Zygophyllaceae family. It is found in extensive, arid, and scorching regions of India. is used in traditional folk medicines as an aphrodisiac, astringent, lithotriptic, diuretic, and urinary disinfectant. however, uneven, pinnae, elliptical leaves. Sprinkled, round, compressed, five-cornered, transverse partitioned carpel fruits with many seeds ripen in July. Pieces of the cylindrical-fibrous root are 7-18 cm and 0.3-0.7 cm wide. According to reported studies, the investigations indicated the presence of the saponins ;gitogenin, tigogenin, neogitogenin, hecogenin, and flavonoid tribuloside was kaempferol-3-glucoside. Furthermore, Tribulus terrestris plays a vital role in hepatotoxicity and is greatly reduced by Tribulus extracts. Similarly, T.terrestris plays a remarkable role in reducing the elevated level of serum glucose, triglycerides, VLDL, and cholesterol. This study aims to conduct a preliminary analysis of the phytochemicals of Tribulus leaves cultivated in Iraq and to determine the active constituent of the ethanolic extract of the leaves using Gc-Mass. Qualitative detection of herbal leaves in Iraqi soil, investigated by GC-MASS revealed important constituents. The funding shows a new compound; dihydrocoumarin and other major constituents neophytadiene and alpha-tocopherol.

Kynurenic Acid Plays a Protective Role in Hepatotoxicity Induced by HFPO-DA in Male Mice.

Following its introduction as an alternative to perfluorooctanoic acid, hexafluoropropylene oxide dimer acid (HFPO-DA) has been extensively detected in various environmental matrices. Despite this prevalence, limited information is available regarding its hepatotoxicity biomarkers. In this study, toxicokinetic simulations indicated that under repeated treatment, HFPO-DA in mice serum reached a steady state by the 4th day. To assess its subacute hepatic effects and identify potential biomarkers, mice were administered HFPO-DA orally at doses of 0, 0.1, 0.5, 2.5, 12.5, or 62.5 mg/kg/d for 7 d. Results revealed that the lowest observed adverse effect levels were 0.5 mg/kg/d for hepatomegaly and 2.5 mg/kg/d for hepatic injury. Serum metabolomics analysis identified 34, 58, and 118 differential metabolites in the 0.1, 0.5, and 2.5 mg/kg/d groups, respectively, compared to the control group. Based on weighted gene coexpression network analysis, eight potential hepatotoxicity-related metabolites were identified; among them, kynurenic acid (KA) in mouse serum exhibited the highest correlation with liver injury. Furthermore, liver-targeted metabolomics analysis demonstrated that HFPO-DA exposure induced metabolic migration of the kynurenine pathway from KA to nicotinamide adenine dinucleotide, resulting in the activation of endoplasmic reticulum stress and the nuclear factor kappa-B signaling pathway. Notably, pretreatment with KA significantly attenuated liver injury induced by HFPO-DA exposure in mice, highlighting the pivotal roles of KA in the hepatotoxicity of HFPO-DA.

Bile acid metabolism disorder mediates hepatotoxicity of Nafion by-product 2 and perfluorooctane sulfonate in male PPARα-KO mice

Perfluorooctane sulfonate (PFOS) and Nafion by-product 2 (H-PFMO2OSA) induce hepatotoxicity in male mice via activation of the peroxisome proliferator-activated receptor α (PPARα) pathway; however, accumulating evidence suggests that PPARα-independent pathways also play a vital role in hepatotoxicity after exposure to per- and polyfluoroalkyl substances (PFASs). Thus, to assess the hepatotoxicity of PFOS and H-PFMO2OSA more comprehensively, adult male wild-type (WT) and PPARα knockout (PPARα-KO) mice were exposed to PFOS and H-PFMO2OSA (1 or 5mg/kg/d) for 28d via oral gavage. Results showed that although elevations in alanine transaminase (ALT) and aspartate aminotransferase (AST) were alleviated in PPARα-KO mice, liver injury, including liver enlargement and necrosis, was still observed after PFOS and H-PFMO2OSA exposure. Liver transcriptome analysis identified fewer differentially expressed genes (DEGs) in the PPARα-KO mice than in the WT mice, but more DEGs associated with the bile acid secretion pathway after PFOS and H-PFMO2OSA treatment. Total bile acid content in the liver was increased in the 1 and 5mg/kg/d PFOS-exposed and 5mg/kg/d H-PFMO2OSA-exposed PPARα-KO mice. Furthermore, in PPARα-KO mice, proteins showing changes in transcription and translation levels after PFOS and H-PFMO2OSA exposure were involved in the synthesis, transportation, reabsorption, and excretion of bile acids. Thus, exposure to PFOS and H-PFMO2OSA in male PPARα-KO mice may disturb bile acid metabolism, which is not under the control of PPARα.

Expression profiles of lncRNAs and their possible regulatory role in monocrotaline-induced HSOS in rats.

Aims: Long non-coding RNAs (lncRNAs) contribute to the regulation of vital physiological processes and play a role in the pathogenesis of many diseases. Monocrotaline (MCT) can cause large-scale outbreaks of toxic liver disease in humans and animals in the form of hepatic sinusoidal obstruction syndrome (HSOS). Although many experiments have been carried out to explain the pathogenesis of Monocrotaline-induced hepatic sinusoidal obstruction syndrome and to develop treatments for it, no studies have examined the role of Long non-coding RNAs in this condition. This study aimed to investigate the Long non-coding RNAs-mRNA regulation network in Monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats. Main methods: We established a model for MCT-induced hepatic sinusoidal obstruction syndrome, and then carried out microarray for liver tissues of SD rats in a model of early hepatic sinusoidal obstruction syndrome (12h Monocrotaline treatment vs. control group) to investigate the differentially expressed Long non-coding RNAs and mRNAs in early hepatotoxicity. This was followed by RT-PCR analysis of selected Long non-coding RNAs, which were markedly altered. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome analyses were also conducted. Key findings: 176 Long non-coding RNAs (63 downregulated and 113 upregulated) and 4,221 mRNAs (2,385 downregulated and 1836 upregulated) were differentially expressed in the Monocrotaline-treated group compared to the control group. The biological processes identified in GO enrichment analysis as playing a role in hepatotoxicity were positive regulation of guanosine triphosphate phosphohydrolase, liver development, and the oxidation-reduction process. Pathway analysis revealed that the metabolism pathways, gap junction, and ribosome biogenesis in eukaryotes were closely related to Monocrotaline-induced hepatotoxicity. According to these analyses, LOC102552718 might play an essential role in hepatotoxicity mechanisms by regulating the expression of inositol 1,4,5-trisphosphate receptor-1 (Itpr-1). Significance: This study provides a basis for further research on the molecular mechanisms underlying Monocrotaline-induced hepatotoxicity and its treatment, especially in the early stage, when successful treatment is critical before irreversible liver damage occurs.

Retinoic Acid Potentiates the Therapeutic Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) against Cisplatin-Induced Hepatotoxicity in Rats

(1) Background: Hepatotoxicity is a common health problem, and oxidative stress plays a crucial role in its underlying mechanisms. We inspected the possible effect of retinoic acid (RA) in the potentiation of hepatoprotective effect of bone marrow mesenchymal stem cells (BM-MSCs) against Cisplatin (Cis)-induced hepatotoxicity. (2) Methods: 60 male Sprague Dawley rats (SD) were separated randomly and designated to six main equal groups as follows: (1) Control group, (2) Cis group (rats got Cis 7 mg/Kg i.p.), (3) Cis + vehicle group (as group 2, but rats received the (vehicle) culture media of BM-MSCs), (4) Cis as in group 2 + BM-MSCs (1x106), (5) Cis as for group 2 + RA 1 mg/Kg i.p., and (6) Cis and BM-MSCs as for group 3 + RA as for group 4. Liver injury was assessed by measuring liver enzymes (ALT, AST), while liver toxicity was evaluated by histopathological examination. Apoptotic marker caspase-3 protein was detected immunohistochemically. Real time PCR was performed to detect NADPH oxidase and TNF-α at transcription levels. Oxidative stress was investigated by colorimetric measurement of MDA, GSH and catalase. (3) Results: Contrary to the Cis group (p < 0.05), BM-MSCs/RA supplementation resulted in a substantial decrease in serum levels of hepatic impairment indicators such as ALT, AST and oxidative stress markers such as MDA, as well as an increase in hepatic GSH, Catalase, and a decrease in expression of TNF-α and downregulation of NADPH oxidase. The improvement after therapy with BM-MSCs/RA was confirmed by histopathological examination. Moreover, the downregulation of caspase-3 in liver tissue after BM-MSCs/RA treatment was validated by immunohistochemistry investigation. (4) Conclusions: BM-MSCs and RA attenuated Cis induced hepatotoxicity through downregulation of oxidative stress resulted in modulation of anti-inflammatory TNF-α and apoptosis caspase-3 indicating a promising role in hepatotoxicity.

Biological Role of Pazopanib and Sunitinib Aldehyde Derivatives in Drug-Induced Liver Injury

Tyrosine kinase inhibitors pazopanib and sunitinib are both used to treat advanced renal cell carcinoma but expose patients to an increased risk of hepatotoxicity. We have previously identified two aldehyde derivatives for pazopanib and sunitinib (P-CHO and S-CHO, respectively) in liver microsomes. In this study, we aimed to decipher their role in hepatotoxicity by treating HepG2 and HepaRG hepatic cell lines with these derivatives and evaluating cell viability, mitochondrial dysfunction, and oxidative stress accumulation. Additionally, plasma concentrations of P-CHO were assessed in a cohort of patients treated with pazopanib. Results showed that S-CHO slightly decreased the viability of HepG2, but to a lesser extent than sunitinib, and affected the maximal respiratory capacity of the mitochondrial chain. P-CHO decreased viability and ATP production in HepG2. Traces of P-CHO were detected in the plasma of patients treated with pazopanib. Overall, these results showed that P-CHO and S-CHO affect hepatocyte integrity and could be involved in the pazopanib and sunitinib hepatotoxicity.

Gap junction intercellular communication mediates cadmium-induced apoptosis in hepatocytes via the Fas/FasL pathway.

As a common environmental pollutant, cadmium (Cd) causes damage to many organs of the body. Gap junction intercellular communication (GJIC) represents one of the most important routes of rapid signaling between cells. However, the mechanisms underlying GJIC's role in hepatotoxicity induced by Cd remain unknown. We established a Cd poisoning model in vitro by co-culturing Cd-exposed and unexposed hepatocytes and found that 18β-glycyrrhetinic acid (GA), a GJIC inhibitor, can effectively reduce the apoptosis rate of healthy cells co-cultured with apoptotic cells treated with Cd. We also found that anti-FasL antibody had the same effect. However, in mono-cultured cells, GA treatment in combination with Cd was found to aggravate the damage induced by Cd exposure, increase the level of oxidative stress and protein expression of HO-1, decrease the mitochondrial membrane potential, incur more serious morphological damage to mitochondria than Cd treatment alone. Moreover, compared with Cd-only exposure, GA and Cd co-treatment further increased the expression levels of the apoptosis-related proteins Fas, FasL, FADD and the ratio of Bax/Bcl-2, inhibited the protein expression of ASK1 and Daxx. We also found that the protein expression of Daxx in siFADD + Cd hepatocytes was significantly higher than in Cd-treated cells. Thus, our study suggests that gap junction inhibition may play a dual role in Cd-induced cell damage by inhibiting the transmission of death signals from damaged cells to healthy cells but also aggravating the transmission of death signals between damaged cells, and that the Fas/FasL-mediated death receptor pathway may play an important role in this process.

Nuclear Factor Erythroid-2 Linked Factor (Nrf2) as a Potential Mediator of Hepatotoxicity

Hepatotoxicity is a term used to describe serious health complications of liver disease caused by a variety of factors. Nuclear factor erythroid-2 linked factor (Nrf2) as a potential mediator of hepatotoxicity via inflammatory and induction of oxidative stress, oxidation
 produces more toxic compounds caused more pathogenic cases; therefore, to maintain sufficient homeostasis, involve antioxidant materials and detoxification factors. Controlling cytokine activity in normal cells is a useful way to regulate the signaling pathway of Nrf2. Recent studies found a relation between each Nrf2 and NF-κB activation and drug-induced liver injury. This review presents a detailed and conformation update of Nrf2 roles in hepatotoxicity which considers that drug-induced liver injury is the main problem to draw attention in medical clinics and to develop new drugs with less harmful to the liver. In addition to that. Kept each of normal oxidation and cytokines levels is crucial responses for cells alteration and remaining to survive.

In Vitro and In Vivo Protective Effects of Lentil (Lens culinaris) Extract against Oxidative Stress-Induced Hepatotoxicity

Excessive oxidative stress plays a role in hepatotoxicity and the pathogenesis of hepatic diseases. In our previous study, the phenolic extract of beluga lentil (BLE) showed the most potent in vitro antioxidant activity among extracts of four common varieties of lentils; thus, we hypothesized that BLE might protect liver cells against oxidative stress-induced cytotoxicity. BLE was evaluated for its protective effects against oxidative stress-induced hepatotoxicity in AML12 mouse hepatocytes and BALB/c mice. H2O2 treatment caused a marked decrease in cell viability; however, pretreatment with BLE (25–100 μg/mL) for 24 h significantly preserved the viability of H2O2-treated cells up to about 50% at 100 μg/mL. As expected, BLE dramatically reduced intracellular reactive oxygen species (ROS) levels in a dose-dependent manner in H2O2-treated cells. Further mechanistic studies demonstrated that BLE reduced cellular ROS levels, partly by increasing expression of antioxidant genes. Furthermore, pretreatment with BLE (400 mg/kg) for 2 weeks significantly reduced serum levels of alanine transaminase and triglyceride by about 49% and 40%, respectively, and increased the expression and activity of glutathione peroxidase in CCl4-treated BALB/c mice. These results suggest that BLE protects liver cells against oxidative stress, partly by inducing cellular antioxidant system; thus, it represents a potential source of nutraceuticals with hepatoprotective effects.

The integrated use of in silico methods for the hepatotoxicity potential of Piper methysticum

Herbal products as supplements and therapeutic intervention have been used for centuries. However, their toxicities are not completely evaluated and the mechanisms are not clearly understood. Dried rhizome of the plant kava (Piper methysticum) is used for its anxiolytic, and sedative effects. The drug is also known for its hepatotoxicity potential. Major constituents of the plant were identified as kavalactones, alkaloids and chalcones in previous studies. Kava hepatotoxicity mechanism and the constituent that causes the toxicity have been debated for decades. In this paper, we illustrated the use of computational tools for the hepatotoxicity of kava constituents. The proposed mechanisms and major constituents that are most probably responsible for the toxicity have been scrutinized. According to the experimental and prediction results, the kava constituents play a substantial role in hepatotoxicity by some means or other via glutathione depletion, CYP inhibition, reactive metabolite formation, mitochondrial toxicity and cyclooxygenase activity. Some of the constituents, which have not been tested yet, were predicted to involve mitochondrial membrane potential, caspase-3 stimulation, and AhR activity. Since Nrf2 activation could be favorable for prevention of hepatotoxicity, we also suggest that these compounds should undergo testing given that they were predicted not to be activating Nrf2. Among the major constituents, alkaloids appear to be the least studied and the least toxic group in general. The outcomes of the study could help to appreciate the mechanisms and to prioritize the kava constituents for further testing.

Hepatoprotective activity of depsidone enriched Cladonia rangiferina extract against alcohol-induced hepatotoxicity targeting cytochrome P450 2E1 induced oxidative damage

Alcoholic liver disease (ALD) is a broad-spectrum disorder, covering fatty liver, cirrhosis, alcoholic hepatitis and in extreme untreated condition hepatocellular carcinoma (HCC) may also develop. Cladonia rangiferina (CR) is a class of lichen having a broad spectrum of pharmacological activity. It is used like traditional natural sources in ancient times in India, China, Sri Lanka, etc. Folkloric record about CR has reported their use as an antimicrobial, antitumor, antioxidant, anti-inflammatory activities, etc. Hence, the present study was requested to ascertain the effect of the ethanolic extract of Cladonia rangiferina (CRE) on alcohol-induced hepatotoxicity. The animals were evaluated for the estimation of the liver in vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. The results of this study reveal that CRE proves to be helpful in the treatment of alcohol-induced hepatotoxicity and oxidative stress. Results of different markers have shown that among all, CRE has demonstrated the best hepatoprotective activity. These observations say about the importance of the components of the extract. The ameliorative action of CRE in alcoholic liver damage may exist due to antioxidant, anti-inflammatory, and anti-apoptotic activities.

Formononetin and biochanin A protects against ritonavir induced hepatotoxicity via modulation of NfκB/pAkt signaling molecules

Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity. Five groups of animals were subjected to treatment as control, toxic control (RIT), third group (RIT + FMN), fourth group (RIT + BCA), the fifth group (RIT + FMN + BCA) and sixth group (FMN + BCA) for 14 days. The animals were evaluated for estimation of liver toxicity markers, inflammatory biomarkers, in-vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity. FMN and BCA ameliorated the increased levels of biochemical markers of liver, attenuated the RIT induced Bax, caspase-3, NFκB and eNOS activation and persuaded the Bcl2 and pAkt level. Alteration in the levels of inflammatory markers was also observed in both hepatic tissue and serum. FMN and BCA exerts hepatoprotective effect through modulating the oxidative stress, inflammation, apoptosis and reversing the tissue degeneration suggesting its therapeutic role in hepatotoxicity and other hepatocellular diseases.

Acetaminophen-induced fulminant liver failure (clinical case presentation and a review of the literature)

Acetaminophen (AAP) is one of the most common and widely used antipyretic drugs, but its overdose is the leading cause of fulminant hepatic insufficiency in the world. Mechanisms of liver damage at the use of toxic doses of AAP are caused by the transformation of the isoform of cytochrome P450 (CYP2E1, CYP2A6) into a reactive metabolite, N-acetyl-parabenzoquinonimine (NAPQI), which plays a major role in hepatotoxicity. Another mechanism of hepatotoxicity includes the formation of peroxynitrite – a toxic free radical produced in the mitochondria, which causes oxidative damage. In addition to liver damage in case of acetaminophen poisoning, nephrotoxic effect can occur. Potential mechanisms of nephrotoxicity in overdose of AAP are presented, caused by cytochrome P450, as well as prostaglandin synthetase and enzyme N-deacetylase are described. In the clinical case described by us, the development of fulminant hepatic insufficiency against the background of acetaminophen administration led to the development of a coma along with the kidney damage, however, a stable positive dynamics, was achieved during treatment. In the catamnesis 2.5 years later, there were no signs of fibrosis or cirrhosis of the liver.

Abstract 4925: Curcumin, a polyphenol from the Curcuma longa, prevents mercuric chloride-induced liver damage through reversal of oxidative stress and biochemical changes

Abstract Heavy metals globally exist in the environment, and their prolonged exposure causes various disease including cancer. Mercury is a toxic heavy metal. It has been shown to have multiple adverse effects on human health including the nervous system, renal, cardiovascular, hypertension, and weakening the immune system. It is ranked up among the priority heavy metals those affect human health significantly. In 2013, the United States Environmental Protection Agency reported the higher concentration of mercury in the blood of nearly 1.4 million women of reproductive age, and this increased the risk of learning disabilities associated with in-utero exposure. Due to the major excretory organ in the human body, the liver is the primary target sites for the accumulation of environmental heavy metal such as mercury. Phytochemicals have shown and proved their effectiveness against oxidative stress, inflammation, and cancers of several organs. Curcumin, a bioactive compound of turmeric, has been used for the treatment of several diseases including inflammatory disorders, cancer prevention, and various metal toxicities. Here, we investigate the effect of curcumin treatment on mercuric chloride induced hepatotoxicity using the in-vivo animal model system. For the purpose, experimental rats were administered mercury chloride (0.5mg/kg/body weight/day, orally) with and without curcumin (50 mg/kg body weight/day, orally) treatment in a time-dependent manner (7, 14, and 21 days). At the end of the study, we observed that the accumulation of mercury was higher in the liver of mercuric chloride alone group than the liver of non-curcumin treated rats measured using ICP-AES. A concomitant treatment of curcumin significantly reduces mercury accumulation up to 42-60% (p<0.001). In addition to attenuation of the mercury accumulation, curcumin administration also improves the liver functions as assessed through alteration in the levels of serum biomarkers (AST, ALT, Alkaline phosphatase, and GGT). Next, we evaluated the effect of curcumin on oxidative stress markers lipid peroxidation and glutathione. Numerous studies have been shown that mercury mediated oxidative stress play a significant role in hepatotoxicity. The administration of curcumin significantly reduces lipid peroxidation upto 58% (p<0.001) while restored glutathione level upto 39% (p<0.01) compared with the mercuric chloride alone group. Histopathology observations of the liver also justify the effect of curcumin with biochemical findings. Altogether, our findings indicate that curcumin has potential to inhibit mercury-induced hepatotoxicity and may provide useful insights for the prevention of mercury toxicity. Citation Format: Anshu Agarwal, Prabhu Narayan Saxena. Curcumin, a polyphenol from the Curcuma longa, prevents mercuric chloride-induced liver damage through reversal of oxidative stress and biochemical changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4925.

Study on attenuating hepatotoxicity of Tripterygium wilfordii through compatibility of traditional Chinese medicine compound

With the deepening of the study of toxicology of traditional Chinese medicine, the mechanism of hepatotoxicity caused by Tripterygium wilfordii has been gradually revealed. As one of the characteristics of traditional Chinese medicine, Chinese medicine compatibility show its more reasonable and scientific effect in terms of reducing toxicity. In this paper, the author summarizes the research on the basis and mechanism of toxic substances in T. wilfordii, and sum up the compatibility of traditional Chinese medicine (preparation) to reduce its role of hepatotoxicity, so as to provide reference for the rationality and safety in clinical application of T. wilfordii, thereby reducing liver adverse reactions.

Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA).

Hepatic macrophages play crucial roles in hepatotoxicity. We investigated immunophenotypes of macrophages in liver injury induced in rats by thioacetamide (TAA; 300 mg/kg, intraperitoneal) after hepatic macrophage depletion; hepatic macrophages were depleted by liposomal clodronate (CLD; 10 ml/kg, i.v.) one day before TAA injection. Samples were obtained on post-TAA injection days 0, 1, 2, 3, 5, and 7. TAA injection induced coagulation necrosis of hepatocytes on days 1 through 3 and subsequent reparative fibrosis on days 5 and 7 in the centrilobular area, accompanied by increased numbers of M1 macrophages (expressing cluster of differentiation [CD]68 and major histocompatibility complex class II) and M2 macrophages (expressing CD163 and CD204) mainly on days 1 through 3. TAA + CLD treatment markedly decreased the numbers of M1 and M2 macrophages mainly on days 1 through 3; CD163(+) Kupffer cells were most sensitive to CLD depletion. In TAA + CLD-treated rats, interestingly, coagulation necrosis of hepatocytes was prolonged with more increased levels of hepatic enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) to TAA-treated rats; reparative fibrosis was incomplete and replaced by dystrophic calcification in the injured area, indicating the aggravated damage. Furthermore, in TAA + CLD-treated rats, inflammatory factors (monocyte chemoattractant protein [MCP]-1, interferon-γ, tumor necrosis factor-α, and interleukin-10) and fibrosis-related factors (transforming growth factor-β1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1) were decreased at messenger RNA levels, indicating abnormal macrophage functions. It was clearly demonstrated that hepatic macrophages have important roles in tissue damage and remodeling in hepatotoxicity.

Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats.

Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150mg/kg, 250mg/kg, 500mg/kg per os, for 14days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA-treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA-exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high-dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1922-1934, 2016.

Hepatotoxicity mechanisms of isoniazid: A mini-review.

Isoniazid (INH) is an antituberculosis drug associated with idiosyncratic liver injury in susceptible patients. INH-induced hepatotoxicity remains a significant clinical problem, but the underlying mechanisms are still unclear, despite the growing evidence that INH and/or its major metabolite, hydrazine, play an important role in hepatotoxicity.

The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death

Drug-induced mitochondrial dysfunction has been hypothesized to be an important determining factor in the onset of drug-induced liver injury. It is essential to develop robust screens with which to identify drug-induced mitochondrial toxicity and to dissect its role in hepatotoxicity. In this study we have characterised a mechanistically refined HepG2 model, using a panel of selected hepatotoxicants and non-hepatotoxicants. We have demonstrated that acute metabolic modification, via glucose-deprivation over a 4 h period immediately prior to compound addition, is sufficient to allow the identification of drugs which induce mitochondrial dysfunction, in the absence of cell death over a short exposure (2-8 h) using a plate-based screen to measure cellular ATP content and cytotoxicity. These effects were verified by measuring changes in cellular respiration, via oxygen consumption and extracellular acidification rates. Overall, these studies demonstrate the utility of HepG2 cells for the identification of mitochondrial toxins which act directly on the electron transport chain and that the dual assessment of ATP content alongside cytotoxicity provides an enhanced mechanistic understanding of the causes of toxicity.

Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition

Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague-Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10μM) for 24h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity.