Lead-induced Hepatotoxicity Research Articles

Effect of Chelation Therapy on Lead-induced Hepatotoxicity: A Case Series

Background : Opium use is one of the common causes of lead toxicity. Lead poisoning can lead to hepatic, hematologic, musculoskeletal, neurological, and cardiovascular damages. In this study, we investigated the reversibility of lead-induced liver damage following chelation therapy. Methods : We reviewed the medical records of patients with opium-induced lead poisoning regarding elevation in hepatobiliary enzymes level including Alanine Transaminase (ALT), Aspartate Transaminase (AST), and Alkaline Phosphatase (ALP) to normal level and recorded patients’ age, treatment regimen, liver enzymes level before and after treatment; we also investigated other laboratory findings to rule out other causes of liver enzymes increase. Results : We evaluated 10 male patients with the mean age of 48.3±7.42 years. All patients were referred with the chief complain of abdominal cramps (100%). The mean lead level in patients was 84.48±9.95 µg/dL. The mean serum levels of ALT, AST, and ALP significantly decreased after the treatment with chelating agents ([ALT=117.8±60.22µg/dL-76.9±40.73µg/dL, P=0.022], [AST=100.9±63.96µg/dL-69.9±37.41µg/dL, P=0.028], [ALP=449.8±234.81 µg/dL-338.3±131.22µg/dL, P=0.037]). There was no significant correlation between patients’ lead level and liver enzymes level before and after the treatment. Conclusion : The results of this study showed that the treatment with chelating agents reverses the liver injury following the lead intoxication.

PROTECTIVE EFFECT OF SYNTHETIC ANTIOXIDANTS AND ETHANOLIC EXTRACT OF BACOPA MONNIERI AGAINST LEAD TOXICITY INDUCED METABOLIC DYSFUNCTIONS IN MICE BRAIN AND LIVER HOMOGENATES: AN IN VITRO APPROACH

Objective: The main objective of the present study was to investigate the ameliorative potential of synthetic antioxidants mixture comprising N-acetyl cysteine, ascorbic acid, tocopheryl acetate, and thiamine as micronutrient combinational therapy and ethanolic extract of Bacopa monnieri as herbal antioxidant therapy approach against lead toxicity-induced metabolic dysfunctions in vitro.
 Methods: Experimental study involved in vitro exposure of mice brain and liver homogenates to different doses (100 μM, 250 μM, and 500 μM) of lead acetate. The study also involved coadministration of high-dose lead acetate (500 μM) and specific dosage of synthetic antioxidants or ethanolic extract of B. monnieri separately to homogenate cultures. Alterations in metabolic parameters of protein levels and lipid peroxidation were analyzed for evaluating the protective effect of synthetic antioxidants and B. monnieri against lead intoxication.
 Results: Results revealed dose-dependent statistically significant (p<0.001) reduction in protein levels and elevation in lipid peroxidation in lead acetate exposed mice brain and liver homogenates as compared to their respective control groups. Coadministration of lead acetate and synthetic antioxidants mixture or B. monnieri in the brain and liver homogenates conferred protection and manifested maintenance of studied biochemical parameters nearest to control groups. Ameliorative efficacy of B. monnieri against lead-induced neurotoxicity and hepatotoxicity was found to be more pronounced than that of a mixture of synthetic antioxidants.
 Conclusion: Synthetic antioxidants mixture (N-acetyl cysteine, ascorbic acid, tocopheryl acetate, and thiamine) and B. monnieri exhibited remarkable therapeutic efficacy against lead toxicity-induced metabolic dysfunctions in mice brain and liver homogenates by virtue of their antioxidant, neuroprotective, and hepatoprotective abilities.

Grape seed procyanidin extract ameliorates lead-induced liver injury via miRNA153 and AKT/GSK-3β/Fyn-mediated Nrf2 activation

Lead-induced hepatotoxicity is characterized by an extensive oxidative stress. Grape seed procyanidin extract (GSPE) possesses abundant biological activities. Herein, we investigated the protective role of GSPE against lead-induced liver injury and determined the potential molecular mechanisms. In vivo, rats were treated with/without lead acetate (PbAc) (0.05%, w/v) in the presence/absence of GSPE (200 mg/kg). In vitro, hepatocytes were pretreated with/without GSPE (100 μg/ml) in the presence/absence of PbAc (100 μM). PbAc administration to rats resulted in anemia, liver dysfunction, lead accumulation in the bone and liver, oxidative stress, DNA damage and apoptosis. GSPE significantly attenuated these adverse effects, except lead accumulation in liver. GSPE also decreased the expression of miRNA153 and increased the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and levels of its downstream protein, and protein kinase B (AKT) phosphorylation in PbAc-induced liver injury. In primary hepatocytes treated with PbAc, GSPE increased hepatocyte viability and decreased lactate dehydrogenase release and reactive oxygen species levels. Dietary GSPE attenuated PbAc-induced liver injury in rats via an integrated mechanism associated with the miRNA153 and AKT/glycogen synthase kinase 3 beta/Fyn-mediated Nrf2 activation.

The β-1,3-glucan alleviated the hepatotoxicity induced by combination of fipronil and lead in common carp (Cyprinus carpio)

The β-1,3-glucan exerts potential antioxidant effect in experimental animal models, but its role in the protection against fipronil and lead-induced toxicity in fish has not been investigated. In this study, we tested the β-1,3-glucan role against fipronil and lead-induced hepatotoxicity in Cyprinus carpio. Two hundred seventy C. carpio were divided into six groups: control, β-1,3-glucan (0.1 %), fipronil (0.0428 mg/L), lead nitrate (7.3 mg/L), coadministered (fipronil and lead), and coadministered β-1,3-glucan treated. Macrocytic hypochromic anemia with significant decrease in the hepatic antioxidant activities (catalase—CAT, superoxide dismutase—SOD, and glutathione—GSH) and significant increase in the malondialdehyde (MDA) level was observed in fipronil, lead, and the coadministered groups. Moreover, a relative decrease in the level of gene expression (SOD, CAT, glutathione S-transferase—GST, glutathione peroxidase—GPx, and glutathione reductase—GR) was observed. The coadministered β-1,3-glucan-treated group showed an improvement in the erythrocytic pictures, increased hepatic antioxidant activities with a decrease in the MDA level. An improvement in the transcriptional level of SOD, CAT, GST, GPx, and GR was detected. The histopathological finding confirmed the obtained results. It could be concluded that β-1,3-glucan has a hepatoprotective effect against coadministration of fipronil and lead-induced hepatotoxicity in common carp (C. carpio).

Effects of isoquinoline alkaloid berberine on lipid peroxidation, antioxidant defense system, and liver damage induced by lead acetate in rats

Objectives: Liver is considered a target organ affected by lead toxicity. Oxidative stress is among the mechanisms involved in liver damage. Here we investigated the effects of the natural alkaloid berberine on oxidative stress and hepatotoxicity induced by lead in rats.Methods: Animals received an aqueous solution of lead acetate (500 mg Pb/l in the drinking water) and/or daily oral gavage of berberine (50 mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical, molecular, and histological evaluations.Results: Lead-induced oxidative stress, shown by increasing lipid peroxidation along with a concomitant decrease in hepatic levels of thiol groups, total antioxidant capacity, the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase, and reduced versus oxidized glutathione ratio. Berberine corrected all the disturbances in oxidative stress markers induced by lead administration. Berberine also prevented the elevated levels of enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) and the decrease in body weight and albumin. The protective effects of berberine were comparable with silymarin. Furthermore, berberine attenuated liver damage, shown by decreased necrosis and inflammatory cell infiltration.Discussion: Berberine represents a potential therapeutic option against lead-induced hepatotoxicity through inhibiting lipid peroxidation and enhancing antioxidant defenses.Conclusion: Berberine exerted protective effects on lead-induced oxidative stress and hepatotoxicity in rats.

Bioactive peptide carnosin protects against lead acetate-induced hepatotoxicity by abrogation of oxidative stress in rats

abstractContext Oxidative stress is a common mechanism of liver injury. Carnosine is a dipeptide having strong antioxidant effects.Objectives We investigated the effects of carnosine on lead-induced hepatotoxicity and oxidative stress in rats.Materials and methods Animals received an aqueous solution of lead acetate (500 mg Pb/L in the drinking water) and/or daily oral gavage of carnosine (10 mg/kg) for 8 weeks. Rats were then weighed and used for the biochemical (commercial kits), molecular (standard chemical methods) and histological (microscopic) evaluations.Results Lead-induced oxidative stress in liver tissue was indicated by a significant increase in the level of malondialdehyde (MDA) (8.25 ± 0.15 nmol/mg) as well as decrease in the level of total antioxidant capacity (TAC) (1.72 ± 0.25 μmol/g) and total thiol (SH) groups) 1.9 ± 0.22 μmol/g). Carnosine treatment decreased MDA (4 ± 0.08 nmol/mg), whereas it increased the contents of total thiol (3.25 ± 0.04 μmol/g) and TAC (3.44 ± 0.32 μmol/g) in the lead group. Carnosine also prevented the decreased body weight (p < 0.001), albumin (p < 0.05) and total protein levels (p < 0.001) and increased liver weight (p < 0.05) and activates of hepatic enzymes (p’s < 0.001) (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase) in the lead group. Furthermore, histopathological study showed that carnosine attenuates liver damage by decreasing necrosis and infiltration of inflammatory cells.Conclusion Carnosine prevented lead-induced hepatotoxicity, indicated by molecular, biochemical and histopathological analyses through inhibiting lipid peroxidation and enhancing antioxidant defence systems. Therefore, carnosine makes a good candidate to protect against the deleterious effect of chronic lead intoxication.

Lead-Induced Damage on Hepatocytes and Hepatic Reticular Fibres in Rats; Protective Role of Aqueous Extract of &amp;lt;i&amp;gt;Moringa oleifera&amp;lt;/i&amp;gt; Leaves (Lam)

This study was designed to evaluate the hepatoprotective and ameliorative effects of aqueous extract of Moringa oleifera (MO) leaves on the histologyof liver and hepatic reticular fibres integrity of adult Wistar rats following lead-induced hepatotoxicity. Twenty four adult Wistar rats, weighing 180 - 220 g, randomly assigned into four groups of six animals each were used for the study. Lead and Moringa oleifera were given orally to the rats. 24 hours after the last administration, animals were sacrificed, blood obtained by cardiac puncture and liver excised, fixed in 10% phosphate buffered formalin for histological and histochemical analysis. The activities of aspartate amino transferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were used as markers of hepatotoxicity and catalase (CAT) activity were used as marker to evaluate the anti-oxidant status of the tissue. Result showed that lead treatment increased markers of hepatic damage (ALT, AST and ALP) and decreased CAT activities. Histological studies reveal alterations of hepatic structure including hepatocytic vacuolations, sinuosoidal congestion and loss of reticular fibres following lead treatment. Treatment with MO prevented and reversed lead induced hepatic damage. In conclusion, this study shows that Moringa oleifera leaf extract has an appreciable ability to prevent hepatotoxicity caused by lead, partly as result of its chemical constituents which has hepatoprotective properties.

Thiamine and pyridoxine supplementations ameliorate subchronic lead-induced hepatotoxicity and nephrotoxicity: single action and cocktail effect analysis

The study investigated the role of thiamine and pyridoxine individually and in cocktail in mitigating the biochemical alterations induced by subchronic administration of 500mg/kg of lead acetate for 6 weeks. Twenty – five Wistar albino rats divided into five groups of five animals in each group were used for this study. The first group, the negative control, received no treatment. The second group, the positive control, had 500mg of lead acetate added per kg of feed. The three other groups were given the same regimen as the second group but in addition, 300mg of thiamine per kg diet was added to the third group, 300mg of pyridoxine per kg diet added to the fourth group and 300mg of vitamin mixture containing 150mg of thiamine as well as 150mg of pyridoxine was added per kg diet to the fifth group. The rats were sacrificed after 6 weeks and sera were analysed for alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) activities. Urea and creatinine concentrations were also evaluated. The activities of ALT, AST and ALP as well as the levels of urea and creatinine were significantly lower in all groups that received vitamin supplementation when compared with the positive control. This indicates that thiamine, and pyridoxine has ameliorative effect on lead induced toxicity on liver and kidney of Wistar albino rats. The significant difference between the cocktail group and other individual vitamin groups also showed an additive effect when thiamine and pyridoxine are administered in combination.

Cholestasis and Seizure Due to Lead Toxicity: A Case Report

IntroductionLead poisoning is a major public health risk which may involve major organs. Recently, there have been reports of opioid adulteration with lead in Iran. The following case report is the first of its kind in that intrahepatic cholestasis due to lead toxicity has been described.Case PresentationA 65-year-old man presented to the emergency department with abdominal pain, abnormal liver function tests (cholestatic pattern), and normocytic anemia. He had been an opium user for 20 years. Clinical and preclinical findings including the bluish discoloration of periodontal tissues, or Burton’s sign, and generalized ileus on abdominal x-ray led us to the possibility of lead poisoning. Lead levels were higher than normal (150 μg/dL). Magnetic resonance cholangiopancreatography (MRCP) and abdominal ultrasound were performed to rule out extra hepatic causes of cholestasis. To evaluate the possibility of lead-induced hepatotoxicity, a liver biopsy was performed. Histological features of lead-induced hepatotoxity have rarely been described in humans. In this patient, focal canalicular cholestasis and mild portal inflammation were confirmed. Thus, treatment with ethylenediaminetetraacetic acid (EDTA) and British anti-lewisite (BAL) were initiated and continued for five days. The patient’s liver function tests returned to their normal values, clinical findings including nausea, vomiting, and abdominal pain subsided, and the patient was discharged from the hospital in good condition.ConclusionsLead toxicity should always be taken into account in cases of intrahepatic cholestasis with an unknown etiology, especially in a setting where opium abuse is common.

English

Humans are exposed to a number of toxic elements in the environment. Lead, widely used in industry, is a great environmental health problem of both humans and animals. Effects of reactive oxygen species (ROS) generation have been postulated to be major contributors to lead-exposure related disease. Effects of aqueous solution of whole ginger on hepatic injury due to lead-induced oxidative stress in experimental rats have been investigated. Lead acetate (LA) at a dose of 500 ppm in drinking water was administered to rats for 50 days to induce hepatic injury. Freshly prepared aqueous whole ginger solution at a dose of 160 mg/kg body weight was administered orally to rats. Lead acetate treatment caused hepatic injury as evident from increased activities of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) atrnd alkaline phosphatase (ALP), depleted hepatic reduced glutathione (GSH) and elevated hepatic malondialdhyde (MDA) concentration. Lead-induced oxidative stress in liver was evident from increased levels of lipid peroxidation and reduced level of GSH. The decreased activity of glutathione peroxidase (GPx) indicates possible accumulation of ROS. The changes in AST and GPx activities and MDA concentration were found to be mitigated when the rats were treated with whole ginger. Also, ginger treatment of LA-exposed rats was found to enhance superoxide dismutase (SOD) activity. Results indicate that ginger has the potential to ameliorate lead-induced hepatic injury due to oxidative stress in rats. Ginger may exert its protective actions against lead-induced hepatotoxicity in rats possibly through its antioxidant mechanisms and may have future therapeutic relevance. &nbsp; Key words:&nbsp;Lead, ginger, oxidative stress, antioxidants, hepatotoxicity, albino rats.

Protective role of puerarin on lead-induced alterations of the hepatic glutathione antioxidant system and hyperlipidemia in rats

Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. The aim of the present study was to investigate the effects of puerarin on hepatic oxidative stress and hyperlipidemia in rats exposed to lead. Our data showed that puerarin significantly prevented lead-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage (serum aminotransferase levels) and histopathological analysis. Moreover, lead-induced profound elevation of ROS production and oxidative stress, as evidenced by increasing of lipid peroxidation level, reducing of GPx, GST, GR and GCL activities and depleting of intracellular reduced GSH level in liver, were suppressed by treatment with puerarin. Furthermore, the increase of serum cholesterol, triglycerides and LDL induced by lead was effectively suppressed by puerarin. The HDL level in the lead treatment rats was also increased by puerarin. Western blot analysis showed that puerarin remarkably inhibited hyperlipidemia by regulating the expression of cholesterol 7a-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) and low-density lipoprotein receptor (LDL-R) in liver of lead treated rats. Altogether, these results suggest that puerarin could protect the lead-induced liver injury and hyperlipidemia by reducing ROS production, renewing the activities of antioxidant enzymes and influencing expression of hepatic lipid biosynthesis and metabolism genes.

Lead-induced hepatotoxicity and evaluation of certain anti-stress adaptogens in poultry

A total of 225 day-old sexed male broiler chicks (Vencobb strain) were divided randomly into 15 groups consisting of 15 chicks in each group to study the toxicity of lead on hepatocytes. Group 1 was maintained on basal diet, group 2 on polyherbal formulation (PHF; stressroak), group 3 on shilajith, group 4 on amla and group 5 on vit E + Se. Group 6 was maintained on lead for 6 weeks and group 7 on lead for 4 weeks and subsequently on basal diet without lead for the remaining 2 weeks. Groups 8, 9, 10 and 11 were given lead along with PHF, shilajith, amla and vit E + Se, respectively, throughout 6 weeks. Groups 12, 13, 14 and 15 were given lead containing diet for the first 4 weeks and subsequently treated with PHF, shilajith, amla and vit E + Se, respectively, for the remaining 2 weeks. The activity of alanine transaminase (ALT) was significantly (P<0.05) increased in the toxic control groups at the end of 4th week as compared to group 1. However, following treatment, there was a significant (P<0.05) reversal in groups 12–15. The activity of Na+/K+-ATPase, Ca2+ATPase, Mg2+ATPase and CYP450 was significantly (P<0.05) reduced in the liver of toxic control groups 6 and 7 as compared to groups1 through 5, which had the maximum activity of all the groups. Groups 8 through 15 revealed a significant (P<0.05) increase in the activity of these hepatocytic enzymes. The histological sections of the liver in lead toxic control (group 6) showed moderate focal lymphoid aggregates in liver, whereas the lesions were mild to moderate in treated groups and there were no observable lesions in plain control groups. The study revealed protective effect of PHF (stressroak), shilajith, amla and vit E + Se in lead-induced hepatocytic damage.

The Redox Status in Rats Treated with Flaxseed Oil and Lead-Induced Hepatotoxicity

Lead is a persistent environmental pollutant, and its toxicity continues to be a major health problem due to its interference with natural environment. In the present study, we have evaluated the effect of flaxseed oil on lead acetate-mediated hepatic oxidative stress and toxicity in rats. Lead acetate enhanced lipid peroxidation and nitric oxide production in both serum and liver with concomitant reduction in glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione-S-transferase, and glutathione peroxidase activities, these findings were associated with DNA fragmentation. In addition, lead acetate caused liver injury as indicated by histopathological changed of the liver with an elevation in total bilirubin, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, and alkaline phosphatase. Treatment of rats with flaxseed oil resulted in marked improvement in most of the studied parameters as well as histopathological features. On the basis of the above results it can hypothesized that flaxseed oil is a natural product can be protect against lead acetate-mediated hepatic cytotoxicity.

Protective effect of Etlingera elatior (torch ginger) extract on lead acetate--induced hepatotoxicity in rats.

Lead is known to disrupt the biological systems by altering the molecular interactions, cell signaling, and cellular function. Exposure to even low levels of lead may have potential hazardous effects on brain, liver, kidneys and testes. The efficacy of Etlingera elatior (torch ginger) to protect hepatotoxicity induced by lead acetate was evaluated experimentally in male Sprague - Dawley rats. Rats were exposed to lead acetate in drinking water (500 ppm) for 21 days and the effects of concurrent treatment with extract of E. elatior on hepatic lipid hydroperoxides (LPO), protein carbonyl content (PCC), total antioxidants (TA), superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione S- Transferase (GST) levels and histopathological changes in liver were evaluated. There was a significant decrease in TA and other antioxidant enzymes (p < 0.05) and increase in LPO and PCC (p < 0.05) with lead acetate ingestion. Concurrent treatment with E. elatior extract significantly reduced the LPO and PCC (p < 0.05) in serum and increased the antioxidant enzyme levels (p < 0.05) in the liver. Significant histopathological changes were seen in hepatic tissue with chronic lead ingestion. Treatment with E. elatior significantly reduced these lead-induced changes in hepatic architecture. E. elatior has also reduced the blood lead levels (BLL). Thus, there has been extensive biochemical and structural alterations indicative of liver toxicity with exposure to lead and E. elatior treatment significantly reduced these oxidative damage. Our results suggest that E. elatior has a powerful antioxidant effect against lead-induced hepatotoxicity.

Protective role of Tinospora cordifolia against lead-induced hepatotoxicity

The importance of Tinospora cordifolia stem and leaves extract was investigated for its possible hepatoprotective effect in Swiss albino male mice against lead nitrate induced toxicity. Oral administration of plant extracts prevented the occurrence of lead nitrate induced liver damage. The decreased level of tissue enzymes, i.e., superoxide dismutase (SOD), catalase (CAT) and increased level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and acid phosphatase (ACP) were observed in mice treated with lead. Administration of aqueous stem extract (400 mg/kg body weight, orally) and aqueous leaves extract (400 mg/kg body weight, orally) along with the lead nitrate (5 mg/kg body weight, i.p. for 30 days) increased the activities of SOD and CAT and decreased the levels of AST, ALT, ALP, and ACP enzymes in mice. These biochemical observations were supplemented by histopathology/histological examinations of liver section. Results of this study revealed that plant extract could afford protection against lead-induced hepatic damage.

Amelioration of lead-induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

Lead is a blue–gray and highly toxic divalent metal that occurs naturally in the earth's crust and is spread throughout the environment by various human activities. The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oral treatment with lead nitrate at a dose of 50 mg/kg body weight daily for 40 days (1/45 of LD50) induced a significant increase in the levels of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, cholesterol, lipid peroxidation, and lead nitrate. In parallel, hepatic protein levels in lead-exposed mice were significantly depleted. Lead nitrate exposure also produced detrimental effects on the redox status of the liver indicated by a significant decline in the levels of liver antioxidants such as superoxide dismutase, catalase, and glutathione. After exposure to lead nitrate (50 mg/kg body weight for 10 days), the animals received aqueous garlic extract (250 mg/kg body weight and 500 mg/kg body weight) and ethanolic garlic extract (100 mg/kg body weight and 250 mg/kg body weight), and partially restored the deranged parameters significantly. Histological examination of the liver also revealed pathophysiological changes in lead nitrate-exposed group and treatment with garlic improved liver histology. Our data suggest that garlic is a phytoantioxidant that can counteract the deleterious effects of lead nitrate.