Changes In Liver Enzyme Activities Research Articles

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

Biochemical and histopathological effects of sub-acute exposure of albino rats to fumigants - dichlorvos and cypermethrin.

Cypermethrin (CYP) is one of the most common active ingredients in most insecticides, mosquito coils and powder used in Nigeria. dichlorvos (DDVP) is the most indiscriminately used fumigant in most rural and sub-urban areas in Nigeria. These fumigants can easily be accessed without proper method of usage thus exposing the population to their toxic effects. As a result, this study was initiated to determine the effects of sub-acute exposure of CYP and DDVP on some biochemical and histopathological parameters of albino rats. In this study, forty (40) albino rats of 10 groups of 4 rats per group, with one group serving as control, were exposed to these fumigants in a poorly ventilated area for 4hours per day over 2, 4 and 6 weeks. The results showed observable changes in liver enzyme activities (p<0.05) in groups exposed to DDVP for 2, 4 and 6 weeks. The groups exposed to CYP showed mild changes in liver enzyme activities when compared with the DDVP groups. Increase in activity of the liver enzymes was also observed in the groups exposed to a mixture of DDVP+CYP for 2, 4 and 6 weeks. The urea, creatinine and electrolytes levels in all the groups exposed to DDVP, CYP and DDVP+CYP for 2, 4 and 6weeks were significantly (p<0.05) increased. Also WBC and platelets in all the groups exposed to DDVP and CYP recorded significant changes. The histology report of the lungs and liver showed moderate lymphocytic infiltration and hepatocytic steatosis which progressed with duration of exposure to the fumigants, while the kidneys showed no remarkable changes. The results of this study suggest that DDVP and CYP have relative toxic effects in the exposed animals and should be used with caution to avoid human exposure to their visible toxicities.

Cypermethrin Induced Liver Toxicity: Altered Gene Expression and DNA Methylation

Cypermethrin, a type II pyrethroid, is a widely used insecticide worldwide. It is considered a safe insecticide to be used in pet shampoos and household cleaning agents thus ignoring the possible health hazards caused by it. Cypermethrin may contaminate food, water, fruits or get deposited on furniture, mats or floors leading to acute or chronic disorders in non‐target organisms. Very limited studies with low and non‐frequent dose mimicking the unintentional cypermethrin intake in non‐target organisms including human beings have been carried out. The present study was aimed at evaluating the toxic effect of cypermethrin in the liver of Balb/c mice exposed to a low and once in a week oral dose (1/10 LD50) for 28 days. Serum was extracted from blood after the dosing period and utilized for Liver Function Tests. The gene regulatory studies were performed by amplifying the cDNA, employing specific primers for p21 and p53 and other cell cycle regulatory genes through PCR (Polymerase Chain Reaction). DNA methylation studies were carried out by bisulfite treatment of DNA followed by Bisulphite specific PCR. The methylation status was found out by analyzing the gene promoter regions through sequencing.The changes in liver enzyme activities and histo‐architecture of liver cells show that sub‐chronic exposure to cypermethrin causes liver damage. It also induces a significant increase in hepatic markers enzymes (ALT, AST, ALP) along with necrosis, vacuolar degeneration, increased kupffer cells and a decrease in the number of hepatocytes. A significant change in the gene expression of p21 and p53 is seen in the test animals pointing towards the relation of liver injury by cypermethrin with cell cycle regulatory mechanisms. The gene promoter region of p53 gene show alteration in methylation status in the test animal sample as compared to the control.Sub‐chronic exposure to cypermethrin causes significant changes in liver enzyme activities, cell architecture, cell cycle regulatory gene expression and methylation status of the concerned genes. These genes along with the other cell cycle regulatory genes can be used as biomarkers for liver injury caused by low doses of cypermethrin.Support or Funding Information1. University Grant Commission, New Delhi, India.2. DST‐PURSE grant, New Delhi, India.3. Institute of Forensic Science and Criminology, Panjab University, India.4. Centre for Stem cell and Tissue Engineering, Panjab University, India.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cylindrospermopsin toxicity in mice following a 90-d oral exposure

ABSTRACTCylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 µg/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 µg/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.

Incidence, timing, and risk factors of azathioprine hepatotoxicosis in dogs.

BackgroundThe use of azathioprine (AZA) in dogs is limited by the development of hepatotoxicosis and cytopenias.Hypothesis and ObjectivesTo characterize the observed incidence, timing, and risk factors for AZA hepatotoxicosis in dogs treated clinically, and to determine the relationship between the development of hepatotoxicosis and cytopenias.AnimalsFifty‐two dogs treated with AZA with clinical and biochemical follow‐up, with a subset of 34 dogs available for determination of changes in liver enzyme activities in serum.MethodsRetrospective medical record review, from January 2009 through December 2013.ResultsHepatotoxicosis (as defined by a >2‐fold increase in serum ALT) was observed in 5 of 34 dogs (15%) within a median onset of 14 days (range, 13–22 days). Dogs had a median 9‐fold increase in ALT and 8‐fold increase in ALP, which stabilized or resolved with drug discontinuation or dose reduction. German shepherds were significantly over‐represented (3 of 5 dogs with hepatotoxicosis; P = .0017). Thrombocytopenia or neutropenia were seen in 4 of 48 dogs with CBC follow‐up (8% of dogs), but occurred significantly later in treatment (median onset, 53 days; range 45–196 days) compared to hepatotoxicosis (P = .016).Conclusions and Clinical ImportanceThese results support the routine monitoring of liver enzymes during the first 1–4 weeks of AZA treatment in dogs, with continued monitoring of the CBC. Additional studies are warranted to characterize the apparently higher risk of AZA hepatotoxicosis in German shepherds.

Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats

The present study was undertaken to evaluate the protective effect of selenium against arsenic-induced oxidative damage in experimental rats. Males were randomly divided into four groups where the first was served as a control, whereas the remaining groups were respectively treated with sodium selenite (3 mg/kg b.w.), sodium arsenite (5.55 mg/kg b.w.) and a combination of sodium arsenite and sodium selenite. Changes in liver enzyme activities, thiobarbituric acid reactive substances (TBARS) level, antioxidants and reduced glutathione (GSH) contents were determined after 3 weeks experimental period. Exposure of rats to As caused a significant increase in liver TBARS compared to control, but the co-administration of Se was effective in reducing its level. The activities of glutathione peroxidase (GPx) and glutathione-S-transferase (GST) of As-treated group were found lower compared to the control and the Se-treated group. The co-administration of Se had an additive protective effect on liver enzyme activities compared to As-treated animals. On the other hand, a significant increase in plasmatic activities of AST, ALT and ALP was observed in As-treated group. The latter was also exhibited a decrease in body weight and an increase in liver weight compared to the control. The co-administration of Se has decreased the activities of AST, AST and ALP and improved the antioxidant status as well. Liver histological studies have confirmed the changes observed in biochemical parameters and proved the beneficial role of Se. To conclude, results suggest that As exposure enhanced an oxidative stress by disturbing the tissue antioxidant defense system, but the Se co-administration protected liver tissues against As intoxication probably owing to its antioxidant properties.

Hepatoprotective Action of Zerumbone Against Paracetamol Induced Hepatotoxicity

This study is conducted to investigate the possible effect of zerumbone towards hepatoprotective activity against paracetamol intoxication. Male Sprague-Dawley rats were randomly divided into six groups consisted of 3-5 animals. Group I was administered with 0.2% zerumbone for 14 days prior to 3 g kg-1 paracetamol administration. Group II was given paracetamol early and group III was given 200 mg kg-1 of silymarin and paracetamol. Group IV was administered with zerumbone only and finally group V was treated with corn oil and 40% sucrose buffer as vehicle treated group. Animals were sacrificed at 4 and 24 h post treatment following diethyl ether. There was no significant changes in liver enzyme activities as well as histological observations at 4 h after paracetamol administration. Meanwhile, 24 h after paracetamol administration, the level of alanine aminotransferase (ALT), aspartate aminotransferase. (AST) and alkaline phosphatase (ALP) were found to be reduced in rats that were pretreated with zerumbone compared to group that was treated with paracetamol only. Correspondingly, there was no hepatocellular necrosis observed in rats that were pretreated with zerumbone. The results obtained may have suggested that zerumbone exert hepatoprotective activities against paracetamol induced hepatotoxicity.

Changes in Liver Enzyme Activities in African Catfish (Clarias gariepinus) Exposed to Crude Oil

The biochemical assessment of the effect of crude oil polluted water on some liver enzymes of African catfish (Clarias gariepinus) was carried out. A total of 30 active (mobile) juvenile catfish of average weight of 75.33 ± 3.0g were divided into six groups of five catfish and held for 30 hour in five different crude oil contaminated aqueous solutions (0.1%, 0.25%, 0.5%, 0.75%, 1.0%). Catfish in the control group were held in borehole water. The results obtained revealed a significant reduction (p 0.05) was obtained in the initial and final weights of control catfish. In comparison to the control, the results showed a significant increase (p<0.05) in the LDH activity and a significant decrease (p<0.05) in the AST and ALT activity of the liver of catfish as the concentration of crude oil increased. The data obtained may be interpreted as a possible adverse effect of crude oil on juvenile catfish as manifested by changes in liver enzymes.

The effect of space flight on the board of the satellite cosmos 2044 on plasma hormone levels and liver enzyme activities of rats

The aim of present experiment was to study the changes of corticosterone, insulin and glucose levels in plasma, of the activity of enzymes involved in aminoacid metabolism in liver and the binding of insulin to specific receptors of cell membrane from liver and also of adipose tissue of rats exposed to space flight for 14 days on biosatellite Cosmos 2044. Adult male Wistar rats (body mass 300–370 g) were divided into five groups: intact control rats (AC), rats exposed to space flight (F), animals in synchronous model experiment (S), rats in antiorthostatic hypokinesia (A) and so called operated control group (C). Half of all groups (5 animals) except the intact control were operated 3 days before the experiment (fibulas on both hind legs were broken). The flight animals were sacrificed 5–6 hours after landing. It was observed that plasma insulin levels are increased in rat exposed to 14-day space flight and in synchron experiments. A significant increase of plasma glucose levels was found in flight rats in spite of high insulin concentrations suggesting that in rats exposed to 14-day space a deterioration of tissue sensitivity to insulin could by present. No significant differences of specific insulin binding to liver plasma membrane fraction in flight and intact control animals were observed. A decrease of insulin binding capacity in liver was found in rats in antiorthostatic hypokinesia (A). However in the membrane of adipocytes an important increase of insulin receptors was noted in rats subjected to space flight. These results suggest, that the liver and adipocyte insulin receptors of flight rats did not respond to the increased plasma insulin levels by “down regulation”. The determination of plasma corticosterone levels showed that in flight rats and in animals exposed to antiorthostatic hypokinesia the plasma hormone levels are significantly elevated. A significant increase of tyrosine aminotransferase and tryptophan pyrrolase activities in liver of flight rats and those exposed to hypokinesia was observed. Also the elevation of alanine aminotransferase in liver was observed in flight rats, while, the activity of aspartate aminotransferase in liver was similar in control and flight animals. These results showed that the changes in liver enzyme activities in rats after 14-day space flight are in agreement with the results observed in previous experiments after a shorter space flight (7 days).

Metabolic and osmoregulatory changes during temperature acclimation in the red sea bream, Chrysophrys major: Implications for its culture in the subtropics

Red sea bream, Chrysophrys major, were acclimated to 10, 20, 25 and 30°C for 21 days in seawater. At the end of the acclimation period, fish were sampled and changes in plasma, liver and muscle composition as well as changes in liver enzyme activities were monitored. Plasma osmolality, and Na +, K + and Mg 2+ concentrations were significantly elevated in fish adapted to 30°C. Plasma total α-amino acids, protein and lipid levels were also significantly higher in warm-acclimated fish. On the other hand, muscle and liver of the warm-acclimated fish had significantly lower amounts of total lipid and protein than the cold-acclimated animals. There was also a trend toward reduction in plasma glucose concentration in fish acclimated to higher temperatures; this was accompanied by a marked increase in liver and muscle glycogen storage. The activities of the key gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,-6-diphosphatase, were markedly elevated in the liver of warm-acclimated fish. However, the activity of glucose-6-phosphate dehydrogenase was markedly elevated at 10°C. These data suggest that the metabolism of the red sea bream has been reorganized in response to temperature acclimation. At high temperatures, enhanced protein and lipid catabolism prevails and glycogen deposition results from elevated gluconeogenesis from protein. Metabolic and ionic disturbances occurring at 30°C suggest that it is undesirable to culture red sea bream at high temperatures. Their culture at low temperatures would have the advantage of conserving body protein at the expense of enhanced carbohydrate utilization.

Changes in liver enzyme activities of glycine metabolism of rats fed excess glycine diets.

Changes in liver enzyme activities of glycine metabolism of rats fed excess glycine diets.

NITROGEN METABOLISM IN COLD-EXPOSED RATS

In these studies, male albino rats were exposed to cold (2–3 °C) for a 7-day period. In vivo studies included the daily measurement of body weight gain, food intake, urine volume, body and liver composition, and nitrogen retention. In vitro, the activities of the following liver enzymes were measured: aspartic acid transaminase, alanine transaminase, arginase, glutamic acid dehydrogenase, and phosphate-activated glutaminase. The results of these experiments demonstrate that exposure of rats to cold increases amino acid catabolism, in part at least to meet increased energy requirements, and reduces protein synthesis as a consequence in the period 2–5 days inclusive, despite a marked increase in food intake. Cold exposure was without effect upon protein absorption but, after 24 hours in the cold, the nitrogen which appeared in the urine increased from about 55% (at 22 °C) to about 76% of the amount that had been absorbed. No effect of cold exposure on nitrogen retention was apparent in the first 24 hours of cold exposure. The subsequent decreased nitrogen retention, on a time basis, appears to bear a relationship to changes in liver enzyme activities, particularly to the increased activities of liver transaminases and arginase.

NITROGEN METABOLISM IN COLD-EXPOSED RATS

In these studies, male albino rats were exposed to cold (2–3 °C) for a 7-day period. In vivo studies included the daily measurement of body weight gain, food intake, urine volume, body and liver composition, and nitrogen retention. In vitro, the activities of the following liver enzymes were measured: aspartic acid transaminase, alanine transaminase, arginase, glutamic acid dehydrogenase, and phosphate-activated glutaminase. The results of these experiments demonstrate that exposure of rats to cold increases amino acid catabolism, in part at least to meet increased energy requirements, and reduces protein synthesis as a consequence in the period 2–5 days inclusive, despite a marked increase in food intake. Cold exposure was without effect upon protein absorption but, after 24 hours in the cold, the nitrogen which appeared in the urine increased from about 55% (at 22 °C) to about 76% of the amount that had been absorbed. No effect of cold exposure on nitrogen retention was apparent in the first 24 hours of cold exposure. The subsequent decreased nitrogen retention, on a time basis, appears to bear a relationship to changes in liver enzyme activities, particularly to the increased activities of liver transaminases and arginase.