P450 2E1 Expression Research Articles

Total sesquiterpene glycosides from Loquat (Eriobotrya japonica) leaf alleviate high-fat diet induced non-alcoholic fatty liver disease through cytochrome P450 2E1 inhibition.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis, which affects 20-40% of the population in the world. Loquat (Eriobotrya japonica) Leaf possesses several pharmacological actions. Many sesquiterpene glycosides were reported to be isolated exclusively from the Loquat Leaf, however, their biological activity has been rarely investigated. The present study was designed to evaluate the pharmacological effect of total sesquiterpene glycosides (TSG) in high-fat diet (HFD) induced NAFLD mice with its related mechanisms of action. Mice were fed with a normal diet or HFD for 8 weeks. TSG (25 and 100mg/kg/day), simvastatin (10mg/kg/day) or vehicle were orally administered for last 4 weeks of the 8-week HFD feeding period. From the result, it was showed that TSG significantly reduced the body weight and fat deposition in the liver of NAFLD mice. It also decreased total cholesterol (TC) and triglyceride (TG) contents in the serum. Compared with NAFLD mice, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were increased and decreased after the administration of TSG in a dose of 100mg/kg, respectively. TSG reduced alanine aminotransferase (ALT) activity as well. Finally, TSG was found to suppress the expression of cytochrome P450 2E1 (CYP2E1) and the phosphorylation of c-jun terminal kinase (JNK) in NAFLD mice. In summary, this study demonstrates that TSG reduces oxidative stress by downregulating of CYP2E1 expression and JNK phosphorylation in NAFLD, and alleviates NAFLD ultimately. TSG potentially serves as bioactive compounds for the treatment of NAFLD.

The TIR/BB-loop mimetic AS-1 prevents non-alcoholic steatohepatitis and hepatic insulin resistance by inhibiting NLRP3-ASC inflammasome activation.

Non-alcoholic steatohepatitis (NASH) is characterized by excessive intracellular lipid accumulation, inflammation and hepatic insulin resistance. As the incidence of NASH is increasing worldwide, there is an urgent need to find novel interventional approaches. The pro-inflammatory cytokine IL-1β, generated and released from Kupffer cells, is considered to initiate the development of NASH. AS-1, a synthetic low-molecule mimetic of myeloid differentiation primary response gene 88 (MyD88), disrupts the interaction between the IL-1 receptor and MyD88. Here, we investigated whether AS-1 could attenuate the pathogenesis of NASH with an emphasis on hepatic insulin resistance. Eight-week-old db/db mice were fed a control diet or a methionine- and choline-deficient (MCD) diet. AS-1 (50mg·kg-1 ) or vehicle was administered i.p. AS-1 administration significantly ameliorated NASH as evidenced by alanine aminotransferase levels and CD68 levels in livers of MCD-fed mice. AS-1 inhibited the MCD diet-induced activation of caspase 1 and the NLRP3-ASC inflammasome, and also reduced the enhanced levels of ROS, malondialdehyde, 3-nitrotyrosine, NADPH oxidase complex and CYP reductase-associated cytochrome p450 2E1 (CYP2E1) expression in the liver. In addition, AS-1 decreased ROS, inflammasome activation and IL-1β production in free fatty acid-LPS-treated Kupffer cells. Finally, pretreatment with AS-1 significantly ameliorated gluconeogenesis and insulin desensitization induced by IL-1β, probably by blocking the interaction between MyD88 and the IL-1 receptor. Our results indicate that AS-1 can ameliorate NASH and hepatic insulin resistance and could be considered as a potential strategy for the prevention and treatment of NASH.

Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines.

Aldose reductase (AR) expression is elevated in the livers of patients with alcoholic liver diseases. However, the role of AR in the development of alcoholic liver diseases remains unclear. The aim of the present study was to determine the effect of AR inhibition on ethanol‑induced hepatosteatosis invivo and invitro, and to identify possible underlying molecular mechanisms. Alcoholic fatty livers were induced in C57BL/6 mice by feeding the mice with Lieber‑DeCarli liquid diets. The expression of AR protein was elevated in the liver tissue of C57BL/6 mice fed with an ethanol diet and in mouse AML12 liver cells exposed to ethanol. In addition to the elevation in AR, hepatic steatosis was observed in ethanol diet‑fed mice, and this ethanol‑induced steatosis was significantly attenuated by inhibiting AR activity with a specific inhibitor, zopolrestat. The suppressive effect of AR inhibition was associated with decreased levels of hepatic lipoperoxides, decreased protein expression of hepatic cytochrome P450 2E1 (CYP2E1), increased phosphorylation of 5'‑AMP‑activated protein kinase (AMPK) and decreased mRNA expression of tumor necrosis factor‑α (TNF‑α). Treatment with the AR inhibitor attenuated the level of lipid accumulation and oxidative stress, activated AMPK, and suppressed the mRNA expression of TNF‑α, interleukin‑6 and transforming growth factor‑β1 in ethanol‑treated AML12 cells. The results of the present study demonstrated that inhibition of AR ameliorated alcoholic liver disease invivo and invitro, in part by activating AMPK, decreasing CYP2E1‑mediated oxidative stress and ameliorating the expression of pro‑inflammatory cytokines.

Enhanced colorectal cancer metastases in the alcohol-injured liver.

Metastatic liver disease is a major cause of mortality in colorectal cancer (CRC) patients. Alcohol consumption is a noted risk factor for secondary cancers yet the role of alcoholic liver disease (ALD) in colorectal liver metastases (CRLM) is not defined. This work evaluated tumor cell colonization in the alcoholic host liver using a novel preclinical model of human CRC liver metastases. Immunocompromised Rag1-deficient mice were fed either ethanol (E) or isocaloric control (C) diets for 4 weeks prior to intrasplenic injection of LS174T human CRC cells. ALD and CRLM were evaluated 3 or 5 weeks post-LS174T cell injection with continued C/E diet administration. ALD was confirmed by increased serum transaminases, hepatic steatosis and expression of cytochrome P4502E1, a major ethanol-metabolizing enzyme. Alcohol-mediated liver dysfunction was validated by impaired endocytosis of asialoorosomucoid and carcinoembryonic antigen (CEA), indicators of hepatocellular injury and progressive CRC disease, respectively. Strikingly, the rate and burden of CRLM was distinctly enhanced in alcoholic livers with metastases observed earlier and more severely in E-fed mice. Further, alcohol-related increases (1.5-3.0 fold) were observed in the expression of hepatic cytokines (TNF-α, IL-1 beta, IL-6, IL-10) and other factors noted to be involved in the colonization of CRC cells including ICAM-1, CCL-2, CCL-7, MMP-2, and MMP-9. Also, alcoholic liver injury was associated with altered hepatic localization as well as increased circulating levels of CEA released from CRC cells. Altogether, these findings indicate that the alcoholic liver provides a permissive environment for the establishment of CRLM, possibly through CEA-related inflammatory mechanisms.

Omega-3 Polyunsaturated Fatty Acids Normalize the Functions of Mitochondria, Pro- and Antioxidant Enzymes of, and Cytochrome P450 2E1 Expression after Isoproterenol-Induced Myocardial Injury

Omega-3 Polyunsaturated Fatty Acids Normalize the Functions of Mitochondria, Pro- and Antioxidant Enzymes of, and Cytochrome P450 2E1 Expression after Isoproterenol-Induced Myocardial Injury

Protective effect of garlic oil on furan-induced damage in the pancreas of adult male rat

Objectives The aim of this study was to investigate the effect of furan on the pancreas of adult male rat and to evaluate the possible protective role of garlic oil (GO). Background Furan is carcinogenic in rats and mice and possibly carcinogenic to humans. Methods Sprague–Dawley rats were divided randomly into four main groups: control, GO (80 mg/kg/day), furan-treated (2 and 8 mg/kg/day), and protected group (furan and GO). All rats were treated orally by a gavage for 5 days per week for 8 weeks. At the end of the experiment, pancreases were subjected to biochemical (measurement of the level of glucose, amylase, lipase, and oxidative stress indices in pancreatic tissue), histological, and immunohistochemical analyses. Results Our results showed the toxic effects of furan on the pancreas in adult male albino rats. This was indicated by an increase in pancreatic (amylase and lipase levels) and lipid peroxidation biomarker (malondialdehyde), and a decrease in antioxidant enzymes, including catalase, superoxide dismutase, and glutathione. In addition, histopathological alterations were detected, including mononuclear cellular infiltration, congestion of blood vessels, and cytoplasmic vacuolation of the acinar cells. There were significant increases in the number of inflammatory cells and apoptotic expression, whereas cytochrome P450 2E1 expression was significantly decreased after the administration of furan. Furan-induced toxicity was ameliorated by the coadministration of GO. Conclusion The administration of furan-induced biochemical and histopathological changes in the pancreas of adult male albino rats. These changes were improved by the coadministration of GO.

Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases

The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP)2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-κB) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury.

Protective effect of wild Corni fructus methanolic extract against acute alcoholic liver injury in mice

ABSTRACTBackground: In Chinese folk medicine, Corni fructus (C. fructus) has traditionally been used to improve liver function, although the mechanism underlying its activity remains unclear. The aim of the present study was to evaluate the protective effects of wild C. fructus methanolic extract against acute alcoholic liver injury.Methods: Alcohol was administered to mice for three consecutive days, either alone or in combination with C. fructus methanolic extract (50, 100, or 200 mg/kg body weight/d). Serum and liver tissue were collected from the animals and subjected to biochemical and histopathological analyses.Results: C. fructus significantly alleviated alcohol-induced liver injury by reducing serum alanine aminotransferase, aspartate aminotransferase, and thiobarbituric acid reactive species, inhibiting hydroxyl radicals (•OH), and increasing total superoxide dismutase, glutathione peroxidase, and glutathione in the liver (P < 0.05). In addition, the C. fructus treatment inhibited the expression and activity of cytochrome P450 2E1 (P < 0.05).Conclusions: C. fructus could be a promising natural substance for ameliorating acute alcohol-induced oxidative stress and hepatic injury.

Diet Supplementation with Allicin Protects against Alcoholic Fatty Liver Disease in Mice by Improving Anti-inflammation and Antioxidative Functions.

This study investigated the liver-protective effects of allicin, an active compound in fresh garlic, against alcoholic fatty liver disease (AFLD) and liver inflammation. Its effects were investigated in an AFLD model in male C57BL/6 mice, which were fed Lieber-DeCarli liquid diet containing ethanol. Allicin (5 and 20 mg/kg bw/day) was orally administered daily in the AFLD mice for 4 weeks. The results indicate that allicin promotes hepatoprotection by significantly reducing aspartate transaminase (AST) and alanine transaminase (ALT) levels (p < 0.05) in the plasma, which are key indicators of liver damage. Allicin reduced fat accumulation, increased glutathione and catalase levels, and decreased microsomal protein cytochrome P450 2E1 (CYP2E1) expression (p < 0.05) in the livers of the AFLD mice. Furthermore, allicin supplementation significantly decreased the levels of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 and suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1) (p < 0.05). Additionally, it improved the hepatic alcohol dehydrogenase (ADH) activity (p < 0.05). Collectively, these findings demonstrate that allicin attenuates liver oxidative stress and inflammation.

Ginsenosides from stems and leaves of ginseng prevent ethanol-induced lipid accumulation in human L02 hepatocytes.

To investigate the effect of ginsenosides from stems and leaves of ginseng on ethanol-induced lipid deposition in human L02 hepatocytes. L02 cells were exposed to ethanol for 36 h and treated with or without ginsenosides. The viability of L02 cells was evaluated by methylthiazolyldiphenyl-tetrazolium bromide assay and the triglyceride (TG) content was detected. Lipid droplets were determined by oil red O staining. Intracellular reactive oxygen species (ROS) production and the mitochondrial membrane potential were tested by flow cytometry. The ATP level was measured by reverse phase high performance liquid chromatography. The expression of cytochrome p450 2E1 (CYP2E1) and peroxisome proliferator-activated receptor α (PPARα) was detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. Ethanol exposure resulted in the increase of TG level, lipid accumulation and ROS generation, and the decrease of mitochondrial membrane potential and ATP production in the cells. However, ginsenosides significantly reduced TG content (9.69±0.22 μg/mg protein vs. 4.93±0.49 μg/mg protein, P<0.01), and ROS formation (7254.8±385.7 vs. 5825.2±375.9, P<0.01). Meanwhile, improvements in mitochondrial membrane potential (10655.33±331.34 vs. 11129.52±262.35, P<0.05) and ATP level (1.20±0.18 nmol/mg protein vs. 2.53±0.25 nmol/mg protein, P<0.01) were observed by treatment with ginsenosides. Furthermore, ginsenosides could down-regulate CYP2E1 expression (P<0.01) and upregulate PPARα expression (P<0.01) in ethanol-treated cells. Ginsenosides could prevent ethanol-induced hepatocyte steatosis in vitro related to the inhibition of oxidative stress and the improvement of mitochondrial function. In addition, the modulation of CYP2E1 and PPARα expression may also play an important role in the protective effect of ginsenosides against lipid accumulation.

Hepatocyte ERBB3 and EGFR are required for maximal CCl4-induced liver fibrosis.

Epidermal growth factor receptor (EGFR) and its ligands have been implicated in liver fibrosis. However, it has not been directly shown that hepatocellular genetic ablation of either this receptor tyrosine kinase or ERBB3, its interactive signaling partner, affects hepatic fibrosis. Carbon tetrachloride (CCl4)-induced liver fibrosis in hepatocyte-specific (HS) mouse models of EGFR and ERBB3 ablation was evaluated in both single gene knockouts and an HS-EGFR-ERBB3 double knockout (DKO). Loss of hepatocellular EGFR or ERBB3 did not impact cytochrome P450-2E1 expression, the extent of centrilobular injury, or the initial regenerative response, but it did diminish liver fibrosis induced by chronic intraperitoneal administration of CCl4 The reduction of liver fibrosis correlated with reduced α-smooth muscle actin expression. Maximal impact to fibrogenesis occurred in the ERBB3 and EGFR-ERBB3 DKO models, suggesting that EGFR-ERBB3 heterodimeric signaling in damaged hepatocytes may play a more important role in liver fibrosis than EGFR-EGFR homodimeric signaling. Immunohistochemical analyses of phospho-EGFR and phospho-ERBB3 isoforms revealed clear staining in hepatocytes, activated stellate cells, and macrophages. Our results support a role for the hepatocellular ERBB tyrosine kinases in fibrogenesis and suggest that pharmacologic inhibition of EGFR-ERBB3 signaling may reverse or retard hepatic fibrosis.

Hepatic expression of cytochrome P450 in Zucker diabetic fatty rats

In this study, the hepatic expression of cytochrome P450 (CYP) enzymes, including CYP1A1/2, 2B1, 2C11, 2E1, 3A1/2, and 4A, was investigated in 5-week-old (insulinresistant state) and 11-week-old (diabetic) Zucker diabetic fatty (ZDF) rats. Serum glucose and glycated hemoglobin levels were increased in 11-week-old ZDF rats, but not in 5-weekold ZDF rats. Hyperinsulinemia was observed in both age groups. The microsomal protein, total CYP, CYP reductase, CYP1A1/2, and CYP3A1 levels did not differ between 5- and 11-week-old ZDF rats and their respective control rats, while CYP4A was up-regulated in both groups. Hepatic levels of cytochrome b5, CYP2B1, CYP2C11, CYP2E1, and CYP3A2 were decreased in 5-week-old ZDF rats, but not in 11-week-old ZDF rats. Similarly, pentoxyresorufin O-depentylase, testosterone 2α- and 16α-hydroxylase, chlorzoxazone 6- hydroxylase, and midazolam 1′- and 4-hydroxylase activities were decreased only in 5-weekold ZDF rats. Based on these results, the 5-week-old ZDF rats exhibited down-regulation of the major CYP enzymes. These results suggest that hepatic expression of CYP enzymes may be dysregulated during development in ZDF rats. With the exception of CYP2B1 and CYP4A, the hepatic levels and activities of CYP were comparable between 11-week-old ZDF and control rats, suggesting that xenobiotic metabolism is normally regulated in the early diabetic state.

Treatment with geraniol ameliorates methionine-choline-deficient diet-induced non-alcoholic steatohepatitis in rats.

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. The aim of this work was to investigate whether treatment with geraniol (a monoterpene) attenuated NASH induced by methionine-choline-deficient (MCD) diet in rats. Rats were fed with MCD diet to induce NASH and treated with geraniol (200 mg/kg/day) for 10 weeks. Treatment with geraniol reduced histological scores, fibrosis, and apoptosis in livers, lowered activities of alanine aminotransferase and aspartate aminotransferase in serum, and attenuated hepatic fat accumulation in rats fed with MCD diet. Treatment with geraniol preserved hepatic mitochondrial function, evidenced by reduced mitochondrial reactive oxygen species formation, enhanced adenosine triphosphate formation and membrane integrity, restored mitochondrial electron transport chain enzyme activity, and increased mitochondrial DNA content in rats fed with MCD diet. Treatment with geraniol reduced uncoupling protein 2 protein expression, and enhanced protein expression of prohibitin, mRNA expression of peroxisome proliferator-activated receptor α, and activity of mitochondrial carnitine palmitoyl transferase-I in livers of rats fed with MCD diet. Treatment with geraniol abated oxidative stress, evidenced by reduced malondialdehyde and 3-nitrotyrosine formation, enhanced activity of glutathione S-epoxide transferase, and down-regulated expression of inducible nitric oxide synthase and cytochrome P450 2E1 in livers of rats fed with MCD diet. Treatment with geraniol reduced myeloperoxidase activity and protein expression of tumor necrosis factor alpha and IL-6 in livers of rats fed with MCD diet. Treatment with geraniol attenuated MCD-induced NASH in rats.

Protective effects of garlic oil against 1,3-dichloro-2-propanol-induced hepatotoxicity: role of CYP2E1 and MAPKs

1,3-Dichloro-2-propanol (1,3-DCP) is a well-known food contaminant that can be detected during the production of a wide range of foods. We investigated whether garlic oil (GO) has protective effects against 1,3-DCP-induced hepatotixicy and oxidative damage in rats. GO significantly attenuated the 1,3-DCP-induced increase in serum aminotransferase activities. This effect was accompanied by attenuation of the histopahological alterations in liver caused by 1,3-DCP. In 1,3-DCP-treated rats, GO prevented formation of hepatic malondialdehyde and depletion of reduced glutathione content, and promoted hepatic antioxidant enzymes activities. 1,3-DCP caused apoptosis in the liver with increases phosphorylation of mitogen-activated protein kinases (MAPKs); GO significantly attenuated these alterations and suppressed the expression of hepatic cytochrome P450 2E1 (CYP2E1). These results suggest that the protective effects of GO against 1,3-DCP-induced hepatotoxicity involve the ability to induce antioxidant enzymes, block metabolic activation of 1,3-DCP by suppressing CYP2E1 expression, and induce antiapoptotic activity by inhibiting phosphorylation of MAPKs.

Antioxidant and Hepatoprotective Effects of Procyanidins from Wild Grape (Vitis amurensis) Seeds in Ethanol-Induced Cells and Rats.

In the present study, we characterized the antioxidant and hepatoprotective mechanisms underlying of wild grape seed procyanidins (WGP) against oxidative stress damage in ethanol-treated HepG2 cell and Sprague-Dawley (SD)-rat models. In HepG2 cells, WGP not only diminished the ethanol (EtOH, 100 mM)-induced reactive oxygen species (ROS) formation and cytochrome P450 2E1 (CYP2E1) expression, but also renovated both the activity and expression of antioxidant enzymes including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, to investigate the hepatoprotective effect of WGP, rats were orally administered 10 or 50 mg/kg WGP once daily for seven days prior to the single oral administration of EtOH (6 g/kg). The results show that WGP administration decreased the EtOH-induced augment of the levels of serum aspartate transaminase and alanine transaminase as well as serum alcohol and acetaldehyde. WGP treatment upregulated the activities and protein levels of hepatic alcohol dehydrogenase, aldehyde dehydrogenase, and antioxidant enzymes but downregulated the protein expression level of liver CYP2E1 in EtOH-treated rats. Moreover, the decreased phosphorylation levels of mitogen activated protein kinases (MAPKs) by ethanol were induced in both HepG2 cell and rat models. Overall, pretreatment of WGP displayed the protective activity against EtOH-mediated toxicity through the regulation of antioxidant enzymes and alcohol metabolism systems via MAPKs pathways.

Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury.

Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP upregulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepatoprotective agent.

Protective role of garlic oil against oxidative damage induced by furan exposure from weaning through adulthood in adult rat testis

Furan is produced in a wide variety of heat-treated foods via thermal degradation. Furan contamination is found to be relatively high in processed baby foods, cereal products, fruits juices, and canned vegetables. Several studies have demonstrated that furan is a potent hepatotoxin and hepatocarcinogen in rodents. However, few studies have investigated the toxic effects of furan in the testis. In addition, the exact mechanism(s) by which furan exerts toxicity in the testis has not been fully elucidated. In this study, we investigated the potential of furan exposure from weaning through adulthood to induce oxidative stress in adult rat testis, as well as the potential of garlic oil (GO) to ameliorate the induced toxicity. Our results reveal that furan administration significantly reduced serum testosterone levels and increased the levels of malondialdehyde (MDA); furthermore, furan administration decreased significantly the enzymatic activity of testicular antioxidants, including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and induced histopathological alterations in the testis. GO co-administration ameliorated the reduction in testosterone levels and dramatically attenuated the furan-induced oxidative and histopathological changes. In addition, Go significantly down-regulated the increased caspase-3 and cytochrome P450 2E1 (CYP2E1) expression in the furan-treated testis. To the best of our knowledge, this study is the first to demonstrate the furan-induced oxidative changes in the adult rat testis and the protective role of GO to ameliorate these changes through its antioxidant effects and its ability to inhibit CYP2E1 production.

Cytochrome P450 2E1 participation in the pathogenesis of experimental metabolic syndrome in guinea pigs.

In this work the experimental metabolic syndrome on the basis of protamine sulfate modeling in guinea pigs was reproduced and pathological processes in the liver of experimental animals were studied. We determined the level of free radicals and markers of liver damage in the blood of experimental animals. We investigated the liver glycogen content and K+,Na+-ATPase activity in the liver of experimental animals as well as measured the cytochrome P450 2E1 (CY P2E1) expression – one of the main factors of oxidative stress. Evidence of development of hepatotoxic processes, increasing of the CY P2E1 level as well as of the free radical level in the animals with metabolic syndrome were found. Using of CY P2E1 inhibitors had shown that the free radical level in the blood of experimental animals depended on the level of the enzyme expression and activity. The obtained results suggest that the changes in the CY P2E1 expression play an important role in the development of hepatotoxic processes upon experimental metabolic syndrome. It was assumed that pharmacological correction of the enzyme expression may be an important mechanism for the influence on the metabolic syndrome clinical course.

Effects of Linderae radix extracts on a rat model of alcoholic liver injury

Traditional treatments have a poor effect on alcoholic liver diseases. Linderae radix (LR), the dried root of Lindera aggregata (Sims) Kosterm., has been frequently used in traditional Chinese medicine for treating various diseases, and has been shown to exhibit a protective effect on liver injury. In the present study, LR extracts were made using various solvents, and then administrated to rats to establish a model of ethanol-induced liver injury. The study aimed to investigate the therapeutic effects and potential mechanism of LR extracts on acute alcoholic liver injury. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycercide (TG), cholesterol (TC), methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD) were determined using an automatic biochemistry analyzer. In addition, pathological examination was performed by hematoxylin-eosin staining. The levels of MDA and SOD, and the expression levels of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in liver tissue were investigated immunohistochemically. The expression of cytochrome P450 2E1 (CYP2E1) mRNA was quantified by reverse transcription-quantitative polymerase chain reaction. The results indicated that LR extracts improved the histopathological status and decreased the serum levels of ALT, AST, TG, TC and MDA. Furthermore, the levels of MDA and inflammatory mediators (NF-κB, TNF-α and IL-1β) were decreased in liver tissues, and the overexpression of CYP2E1 mRNA induced by ethanol treatment. LR extracts exhibited a protective effect on alcoholic liver injury and the mechanism may be associated with the anti-inflammatory and anti-oxidative action.

OMEGA-3 POLYUNSATURATED FATTY ACIDS NORMALIZE THE FUNCTION OF MITOCHONDRIA, ACTIVITY OF ENZYMES OF PROOXIDANT-ANTIOXIDANT SYSTEM AND THE EXPRESSION OF CYTOCHROME Р450 2Е1 AFTER ISOPROTERENOLINDUCED MYOCARDIAL INJURY.

We have studied the influence of dietary ω-3 polyunsaturated fatty acids (ω-3 PUFA) on the functioning of subsarcolemmal and interfibrillar mitochondrial fractions of rat myocardium, changes in expression of cytochrome P450 (CYP2E1) and the activity of enzymes of prooxidant-antioxidant system after isoproterenol-induced myocardial injury. It has been found that in vivo administration of ω-3 PUFA (Epadol 0.1 ml/100 gr of weight for 4 weeks) significantly reduced the swelling of subsarcolemmal and interfibrillar mitochondrial fractions by 65.52% 54.84% respectively, pointing for a decrease of damage of the mitochondrial function evoked by in vivo administration of isoproterenol. In vivo administration of ω-3 PUFAs prevents a decrease in the activity of antioxidant enzymes catalase and superoxide dismutase (2.65 and 7.1- fold, respectively) after isoproterenol-induced myocardial injury. We suggest that the development of oxidative stress after isoproterenol-induced myocardial injury can be caused by a significant increase in the expression of cytochrome P450 2E1 (73.3%), and administration of ω-3 PUFAs prevents such changes.