الفهرس 
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Abstract
A broad range of chemicals are injurious to the liver. Although drug induced liver injury is rare in the general population, it has become more prevalent in hospitalized patients, especially among patients with unexplained liver conditions. Drug induced liver injury is classified into intrinsic hepatotoxicity, idiosyncratic hepatotoxicity and the newly proposed indirect injury. The phenotype of drug induced liver injury is complex, including almost all currently known types of liver injury, ranging in severity from asymptomatic elevations in liver biochemistries to jaundice, fulminant liver failure or even death Drug induced liver injury biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The fundamental process in drug induced liver injury is the death of hepatocytes (in some circumstances, cholangiocytes or endothelial cells) in the background or recruitment of inflammation. To defend against the hazards induced by drugs, hepatocytes exhibit adaptive mechanisms. Ultimately, the battle between hazardous and adaptive responses determines the development of severe injury, restoration of the liver after mild injury (so-called adaptation) or no injury at all. Lithium Carbonate which is commonly used in the treatment of bipolar disorders can cause a certain degree of liver injury, evidenced by increased levels of liver transaminases. This is done by production of toxic free radicals during its liver metabolism, which directly inhibit Na+ - K+ − ATP enzyme activities in liver cells, thus reducing the stability of the liver 157 cell membranes and detoxification enzymes and resulting in elevated transaminase levels and chronic liver damage. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for drug induced liver injury treatment. According to our study, flavonoids as chrysin has good hepatoprotective activity and good effects on drug-induced liver injury, as it can inhibit lipid peroxidation, promote the recovery of the liver cell membrane, eliminate oxygen free radicals, inhibit mitochondrial dysfunction, ameliorate cholestasis, and inhibit the secretion of inflammatory factors by inhibiting the activity of NF-κB. Furthermore, it causes down regulation of the expression caspase 3. Nuclear Factor Kappa-B (NF-KB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. It plays a key role in regulating the immune response to infection. Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis and Liver injury. CASPASE-3 is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. Lithium carbonate directly acts on the mitochondria responsible for opening of mitochondrial permeability 158 transition pore and thus release cytochrome c, decline mitochondrial membrane potential and activation of Caspase-3. The aim of this study was conducted to present a broader outlook in presenting interplay of selected biomarkers concerning the basic pathophysiology underlying the development of hepatotoxicity, it was dedicated to correlate the significant co-ordination between indices of the oxidative stress, apoptosis and inflammatory mediators via their impact in hepatotoxicity. This may enable the illustration of multidisciplinary mechanisms involved in order to target these systems in therapeutic management strategy. Accordingly, we aimed to investigate the biomechanistic influence of the administration of chrysin on the above mentioned mechanisms influencing hepatotoxicity induced in rats. Materials and methods: The present study was conducted on 40 male albino rats randomly divided into four equal groups comprising 10 rats in each group: A- group I (control group): this group has received vehicle of (0.5% sodium carboxymethylcellulose) for 7 weeks. B- group II (lithium-treated group): this group has received vehicle for 3 weeks then received oral dose of 30 mg/kg of lithium carbonate daily (dissolved in distilled water) for 4 weeks. C- group III (chrysin and lithium treated group): this group has received chrysin at a dose of 100 mg/kg body weight orally (11) dissolved in 0.5% sodium carboxymethyl cellulose for 3 weeks then received oral dose of 30 mg/kg of lithium carbonate daily for 4 weeks. D- group IV (chrysin treated group): this group has receive chrysin at a dose of 100 mg/kg dissolved in 0.5% sodium 159 carboxymethylcellulose for 3 weeks and then received vehicle daily for 4 weeks. The different studied groups were subjected for measurements of the following parameters: A- Serum samples: • Serum alanine aminotransferase (ALT). • Serum aspartate aminotransferase (AST). • Serum alkaline phosphatase (ALP) & • Serum total & direct bilirubin B. Liver were excised and subjected to the following: 1. Histopathologic examination of liver tissue specimens from all groups. 2. Hepatic tissue homogenates: • Colorimetric assay of Malondialdehyde (MDA) level. • Colorimetric assay of superoxide dismutase (SOD) Activity. • Colorimetric assay of reduced glutathione level. • Nuclear factor kappa B (NF-ΚB) level by ELISA . • Caspase- 3 level by ELISA . Results of the present study revealed the following: The development of hepatotoxicity was confirmed by the presence of elevated liver enzymes (ALT, AST), ALP, marked increase in total and direct bilirubin. Additionally the characteristic hepatic histopathological changes comprising marked peri-portal inflammatory infiltrate composed mainly of plasma cells and some lymphocytes with vascular congestion. 160 Lithium induced hepatotoxicity group (group II) revealed statistically significant increase of hepatic Caspase3, NF-KB and MDA levels with significant decrease of SOD activity & reduced glutathione level as compared to other studied groups. There was statistically significant decrease of Caspase3, NF-KB & MDA levels in both the chrysin-lithium treated group (group III) and in the chrysin treated group (group IV) when compared to Lithium induced hepatotoxicity group (group II). Also, there was significant increase of SOD and reduced glutathione levels in both the chrysin-lithium treated group (group III) and in the chrysin treated group (group IV) as compared to Lithium induced hepatotoxicity group (group II).