Metabolic Derangement by Arsenic: a Review of the Mechanisms.

Studies have implicated arsenic exposure in various pathological conditions, including metabolic disorders, which have become a global phenomenon, affecting developed, developing, and under-developed nations. Despite the huge risks associated with arsenic exposure, humans remain constantly exposed to it, especially through the consumption of contaminated water and food. This present study provides an in-depth insight into the mechanistic pathways involved in the metabolic derangement by arsenic. Compelling pieces of evidence demonstrate that arsenic induces metabolic disorders via multiple pathways. Apart from the initiation of oxidative stress and inflammation, arsenic prevents the phosphorylation of Akt at Ser473 and Thr308, leading to the inhibition of PDK-1/Akt insulin signaling, thereby reducing GLUT4 translocation through the activation of Nrf2. Also, arsenic downregulates mitochondrial deacetylase Sirt3, decreasing the ability of its associated transcription factor, FOXO3a, to bind to the agents that support the genes for manganese superoxide dismutase and PPARg co-activator (PGC)-1a. In addition, arsenic activates MAPKs, modulates p53/ Bcl-2 signaling, suppresses Mdm-2 and PARP, activates NLRP3 inflammasome and caspase-mediated apoptosis, and induces ER stress, and ox-mtDNA-dependent mitophagy and autophagy. More so, arsenic alters lipid metabolism by decreasing the presence of 3-hydroxy-e-methylglutaryl-CoA synthase 1 and carnitine O-octanoyl transferase (Crot) and increasing the presence of fatty acid-binding protein-3 mRNA. Furthermore, arsenic promotes atherosclerosis by inducing endothelial damage. This cascade of pathophysiological events promotes metabolic derangement. Although the pieces of evidence provided by this study are convincing, future studies evaluating the involvement of other likely mechanisms are important. Also, epidemiological studies might be necessary for the translation of most of the findings in animal models to humans.

Sodium acetate ameliorates doxorubicin-induced cardiac injury via upregulation of Nrf2/HO-1 signaling and downregulation of NFkB-mediated apoptotic signaling in Wistar rats.

Despite the effectiveness of doxorubicin (DOX) in the management of a wide range of cancers, a major challenge is its cardio-toxic effect. Oxidative stress, inflammation, and apoptosis are major pathways for the cardiotoxic effect of DOX. On the other hand, acetate reportedly exerts antioxidant, anti-inflammatory, and anti-apoptotic activities. This particular research assessed the impact of acetate on cardiotoxicity induced by DOX. Mechanistically, acetate dramatically inhibited DOX-induced upregulation of xanthine oxidase and uric acid pathway as well as downregulation of Nrf2/HO-1 signaling and its upstream proteins (reduced glutathione peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione, and catalase, glutathione reductase). In addition, acetate markedly attenuated DOX-driven rise inTNF-α, NFkB IL-6 and IL-1ß expression, and myeloperoxidase activity. Furthermore, acetate significantly ameliorated DOX-led suppression of Bcl-2 and Ca2+-ATPase activity and upregulation of Bax, caspase 3, and caspase 9 actions. Improved body weight, heart structural integrity, and cardiac function as depicted by cardiac injury markers convoyed these cascades of events. Summarily, the present study demonstrated that acetate protects against DOX-induced cardiotoxicity by upregulating Nrf2/HO-1 signaling and downregulating NFkB-mediated activation of Bax/Bcl-2 and caspase signaling.

Acetate attenuates cyclophosphamide-induced cardiac injury via inhibition of NF-kB signaling and suppression of caspase 3-dependent apoptosis in Wistar rats.

AIM: The goal of the current study was to examine the potential therapeutic effects of sodium acetate on cardiac toxicities caused by cyclophosphamide in Wistar rats. The possible involvement of NF-kB/caspase 3 signaling was also explored. MAIN METHODS: Thirty-two male Wistar rats were divided into four groups at random. (n = 8). The control animals received 0.5 mL of distilled water orally for 14 days, the acetate-treated group received 200 mg/kg/day of sodium acetate orally for 14 consecutive days, and cyclophosphamide-treated rats received 150 mg/kg /day of cyclophosphamide i.p. on day 8, while cyclophosphamide + acetate group received sodium acetate and cyclophosphamide as earlier stated. KEY FINDINGS: Results showed that cyclophosphamide-induced cardiotoxicity, which manifested as a marked drop in body and cardiac weights as well as cardiac weight/tibial length, increased levels of troponin, C-reactive protein, lactate, and creatinine kinase, and lactate dehydrogenase activities in the plasma and cardiac tissue. Histopathological examination also revealed toxic cardiac histopathological changes. These alterations were associated with a significant increase in xanthine oxidase and myeloperoxidase activities, uric acid, malondialdehyde, TNF-α, IL-1ß, NFkB, DNA fragmentation, and caspase 3 and caspase 9 activities in addition to a marked decline in Nrf2 and GSH levels, and SOD and catalase activities in the cardiac tissue. Acetate co-administration significantly attenuated cyclophosphamide cardiotoxicity by its antioxidant effect, preventing NFkB activation and caspase 9/caspase 3 signalings. SIGNIFICANCE: This study shows that acetate co-administration may have cardio-protective effects against cyclophosphamide-induced cardiotoxicity by inhibiting NF-kB signaling and suppressing caspase-3-dependent apoptosis.

Zinc protects against lead-induced testicular damage via modulation of steroidogenic and xanthine oxidase/uric acid/caspase 3-mediated apoptotic signaling in male Wistar rats.

AIM: This study evaluated the effect of lead, with or without zinc co-administration, on steroidogenic and xanthine oxidase (XO)/uric acid (UA)/caspase 3-mediated apoptotic signaling in the testis. MATERIALS AND METHODS: Forty male Wistar rats were divided into four groups at random; vehicle-treated control, zinc-treated, lead-treated, and lead + zinc-treated groups. RESULTS: Lead exposure significantly lowered overall weight gain, testicular, epididymal, seminal vesicle, and prostate weights. Also, lead decreased sperm count, viability and motility but increased the fraction of sperm with aberrant morphology. In addition, lead caused a marked rise in the level of UA and XO activity but a decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), reduced glutathione (GSH) as well as total antioxidant capacity (TAC) levels, and superoxide dismutase (SOD) and catalase activities. Furthermore, lead increased the testicular levels of nuclear factor kappa B (NFkB), interleukin-1beta (IL-1ß), and tumour necrotic factor-alpha (TNF-α), which were associated with an increase in testicular caspase 3 activity and DNA fragmentation as well as a decline in circulating gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and testicular 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD). These were associated with lead-induced degenerative changes in testicular tissues evidenced by shrunken seminiferous tubules, degeneration and sloughing of germ cells. Co-administration of zinc prevented lead-induced testicular injury by ameliorating oxidative stress, apoptosis, and inflammation through downregulation of XO/UA/caspase 3 pathway and upregulation of testicular 3ß-HSD/17ß-HSD. CONCLUSION: This study demonstrated that zinc protected against lead-induced testicular toxicity via the downregulation of XO/UA/caspase 3 signaling.

Atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative damage and apoptosis induced by ovarian ischaemia/reperfusion injury.

BACKGROUND: Oxidative damage is critical in the pathogenesis of ovarian ischaemia/reperfusion (I/R) injury, and statins have been reported to exert antioxidant activity. However, the role of VCAM-1 and xanthine oxidase (XO)/uric acid (UA) in ovarian I/R injury is not known. Also, whether or not atorvastatin exerts antioxidant activity like other statins is unclear. OBJECTIVES: This study investigated the involvement of VCAM-1 and XO/UA in ovarian I/R injury and the likely protective role of atorvastatin. METHODS: Forty female Wistar rats were randomized into sham-operated, ischaemia, ischaemia/reperfusion (I/R), ischaemia and atorvastatin, and I/R and atorvastatin. RESULTS: In comparison with the sham-operated group, atorvastatin blunted ischaemia and I/R-induced distortion of ovarian histoarchitecture and follicular degeneration. Also, atorvastatin alleviated ischaemia and I/R-induced rise in XO, UA, and malondialdehyde, which was accompanied by inhibition of ischaemia and I/R-induced reductions in reduced glutathione level, enzymatic antioxidant activities and increase in myeloperoxidase activity and TNF-α and IL-6 levels by atorvastatin treatment. Additionally, atorvastatin blocked ischaemia and I/R-induced increase in VCAM-1 expression, caspase 3 activity, 8-hydroxydeoxyguanosine level and ovarian DNA fragmentation index. CONCLUSION: For the first time, this study revealed that atorvastatin-mediated downregulation of VCAM-1 and XO/UA/caspase 3 signaling averts oxidative injury, inflammation, and apoptosis induced by ovarian ischaemia/reperfusion injury.

Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats.

BACKGROUND: Although highly active antiretroviral therapy (HAART) is effective in the management of HIV, it has been reported to induce hepatic injury and non-alcoholic fatty liver (NAFLD). However, there is a lack of data on the roles of the adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway and caspase 3 signaling in HAART-induced NAFLD. Also, whether or not zinc confers protection against HAART-induced NAFLD is not known. AIM: This study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAART-induced hepatic lipid accumulation. It also evaluated the possible protective effect of zinc in HAART-induced hepatic lipid accumulation and injury. METHODS: Thirty two male Wistar rats (n = 8/group) were assigned into four groups namely; vehicle-treated (p.o), zinc-treated (3 mg/kg/day of elemental zinc; p.o), HAART-treated (a cocktail of 52.9 mg/kg of Efavirenz, 26.48 mg/kg of Lamivudine, and 26.48 mg/kg of Tenofovir; p.o), and HAART + zinc-treated groups. The treatment lasted for 8 weeks. RESULTS: HAART administration led to increased body weight and hepatic weight, but unaltered hepatic organo-somatic index. HAART exposure also resulted in impaired glucose homeostasis, evidenced by increased fasting blood glucose, hyperinsulinemia, and insulin resistance (IR), increased plasma and hepatic cholesterol and triglycerides, and impaired hepatic function as depicted by elevated hepatic injury markers and reduced glycogen synthase activity and glycogen content. These findings were accompanied by increased plasma and hepatic ADA and XO activities, UA and malondialdehyde levels, inflammatory markers, and caspase 3 activities. However, HAART suppressed plasma and hepatic antioxidant defenses. Furthermore, HAART distorted hepatic histoarchitecture and reduced hepatic sinusoidal diameter. Co-administration of zinc with HAART normalized HAART-induced alterations. CONCLUSIONS: These findings showed that downregulation of the ADA/XO/UA pathway and caspase 3 signalings may rescue the liver from HAART-induced lipid accumulation and injury.

Suppression of glutathione system and upregulation of caspase 3-dependent apoptosis mediate rohypnol-induced gastric injury.

Objectives: This study investigated the impact of rohypnol on gastric tissue integrity.Methods: Forty male Wistar rats were randomized into control, low dose rohypnol-treated, high dose rohypnol-treated, low dose rohypnol-treated recovery and high dose rohypnol-treated recovery groups.Results: Rohypnol caused significant rise in gastric malondialdehyde (MDA), oxidized glutathione (GSSG), nitric oxide (NO), tumour necrotic factor-α (TNF-α), and interleukin-6 (IL-6) levels. Also, rohypnol caused reductions in gastric reduced glutathione (GSH) (as well as GSH/GSSG), and activities of superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), glutathione peroxidase (GPx), cyclo-oxygenase (COX-2). Furthermore, rohypnol upregulated caspase 3 activity and induced gastric DNA damage, evident by a rise in 8-hydroxydeoxyguanosine (8-OHdG) and DNA fragmentation index (DFI) in gastric tissue. These alterations were coupled with reduced gastric weight and distorted gastric cytoarchitecture. Cessation of rohypnol caused a significant but not complete reversal of rohypnol-induced gastric damage.Conclusion: This study revealed that rohypnol induced gastric injury by suppressing glutathione content and COX-2 activity, and upregulating caspase 3-dependent apoptosis, which was partly reversed by rohypnol withdrawal.

Glutamine restores testicular glutathione-dependent antioxidant defense and upregulates NO/cGMP signaling in sleep deprivation-induced reproductive dysfunction in rats.

Oxidative stress has been linked with sleep deprivation (SD)-induced pathological conditions and reproductive dysfunction. On the other hand, glutamine has been established to have antioxidant property. However, the impact of SD, with or without glutamine, on male reproductive function is yet to be elucidated. Thus, this study was designed to investigate the role of SD, with or without glutamine, on male reproductive function and possible associated mechanisms. Ten-week old male Wistar rats weighing 175.6 g± 0.42 were randomly assigned into vehicle that received per os (p.o.) distilled water, glutamine (1 g/kg; po), SD, and SD + glutamine that received treatments as glutamine and SD. Treatment/exposure lasted for 72 h. The results showed that SD led to reduced body weight, seminiferous luminal and epididymal sperm density, low sperm quality, increased testicular and epididymal malondialdehyde, uric acid, DNA fragmentation, and testicular injury markers. In addition, SD caused a reduction in reduced glutathione level and activities of superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, glutathione peroxidase, and glutathione-S-transferase. Also, SD increased tumor necrotic factor-α, interleukin-1ß, and nuclear factor-kappa B levels. Furthermore SD led to impaired libido and erectile dysfunction, and suppression of circulatory nitric oxide, gonadotropins and testosterone, and penile cGMP. However, glutamine attenuated the effects induced by SD. Taken together, the findings of this study demonstrate that SD induces reproductive dysfunction via glutathione-dependent defense depletion and down-regulation of NO/cGMP signaling, which was abolished by glutamine supplementation.

Upregulation of Uric Acid Production and Caspase 3 Signalling Mediates Rohypnol-Induced Cardiorenal Damage.

The global prevalence of illicit drug use is on the increase with attendant complications like cardiorenal collapse. One such substance of abuse is rohypnol. Despite its ban in most countries, it remains a popular substance of abuse. Whether or not rohypnol induces cardiorenal injury and the associated mechanism is yet to be elucidated. Therefore, the present study investigated the effect of rohypnol on cardiorenal integrity and functions, and glucolipid metabolism. Forty-eight male Wistar rats randomized into six groups (n = 8/group) received (per os) vehicle, low-dose (2 mg/kg) and high-dose (4 mg/kg) rohypnol once daily for twenty eight days, with or without a cessation period. Data revealed that rohypnol exposure irreversibly caused insulin resistance, hyperglycaemia, and dyslipidaemia. This was accompanied by reduced cardiorenal mass and impaired cardiorenal cytoarchitecture and function. Furthermore, rohypnol treatment promoted oxidative stress, inflammation, genotoxicity, and decreased cardiorenal activities of Na+-K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase. These alterations were associated with enhanced uric acid generation and caspase 3 activity in the cardiorenal complex. Thus, this study reveals that rohypnol exposure triggers cardiorenal toxicity with incident insulin resistance, glucolipid and cardiorenal proton pump dysregulation, altered redox state, and inflammation via enhancement of uric acid generation and caspase 3-dependent mechanism.

HAART exacerbates testicular damage and impaired spermatogenesis in anti-Koch-treated rats via dysregulation of lactate transport and glutathione content.

Highly active anti-retroviral therapy (HAART) is an effective anti-retroviral cocktail. Similarly, anti-Koch is highly potent against Mycobacterium tuberculosis. However, these drugs have been shown to impair male fertility. This study investigated the impact of HAART and anti-Koch, when used alone and co-administered, on testicular and sperm integrity. Thirty-two adult male Wistar rats were assigned randomly into four groups (n = 8), namely normal control, HAART-treated, anti-Koch-treated, and HAART + anti-Koch-treated. The doses of drugs were the human equivalent doses for rats. Administration was once daily per os and lasted for eight weeks. HAART aggravated anti-Koch-induced reduction in testicular and penile weights. In addition, anti-Koch also led to a distortion of testicular cytoarchitecture, disturbed spermatogenesis, and caused low sperm quality, including sperm dysmotility. More so, anti-Koch led to a significant elevation of uric acid and dysregulation of testicular lactate transport and glutathione content. These events were accompanied by enhanced lipid peroxidation and inflammation of the testicular tissue and reduced testicular and sperm DNA integrity. These adverse effects of anti-Koch were aggravated by co-administration of HAART. Thus, our results infer that HAART exacerbates anti-Koch-induced impairment of spermatogenesis and testicular and sperm toxicity through up-regulation of uric acid generation and dysregulation of lactate transport and glutathione system.

Concomitant administration of HAART aggravates anti-Koch-induced oxidative hepatorenal damage via dysregulation of glutathione and elevation of uric acid production.

Anti-Koch and HAART have been shown to independently induce toxicity to the liver and kidney, albeit available data are few and inconsistent. The present study evaluates the impact of Anti-Koch and HAART, when administered singly and in combination, on hepatic and renal status, and the possible role of adenine deaminase (ADA)/xanthine oxidase (XO) pathway. Anti-Koch and HAART administration were observed to independently impair hepatic and renal functions, diminish glutathione content, and substantially increase lipid peroxidation (MDA) and nitrogen reactive specie (NO). Coherently, these drugs caused significant accumulation of polymorphonuclear leucocytes, up-regulated ADA/XO signaling, increased uric acid production, and enhanced DNA fragmentation in the liver and kidney. Anti-Koch treatment did not significantly alter hepatic and renal levels of nitric oxide nor induce DNA fragmentation in the kidney. Co-administration of anti-Koch and HAART aggravated the observed biochemical alterations. Findings from the histopathological studies of the liver and renal tissues were in agreement with observed biochemical alterations. In conclusion, this report is the first to reveal that anti-Koch and HAART, when administered singly or in combination, attenuate glutathione content and elevate uric acid production in the liver and kidney via upregulation of ADA/XO signaling with resultant oxidative and nitrosative stress, and increased DNA fragmentation.

Impact Effect of Methyl Tertiary-Butyl Ether "Twelve Months Vapor Inhalation Study in Rats".

We investigated the early risk of developing cancer by inhalation of low doses (60 µL/day) of methyl tertiary butyl ether (MTBE) vapors using protein SDS-PAGE and LC-MS/MS analysis of rat sera. Furthermore, histological alterations were assessed in the trachea and lungs of 60 adult male Wistar rats. SDS-PAGE of blood sera showed three protein bands corresponding to 29, 28, and 21 kDa. Mass spectroscopy was used to identify these three bands. The upper and middle protein bands showed homology to carbonic anhydrase 2 (CA II), whereas the lower protein band showed homology with peroxiredoxin 2. We found that exposure to MTBE resulted in histopathological alterations in the trachea and the lungs. The histological anomalies of trachea and lung showed that the lumen of trachea, bronchi, and air alveoli packed with free and necrotic epithelial cells (epithelialization). The tracheal lamina propria of lung demonstrated aggregation of lymphoid cells, lymphoid hyperplasia, hemorrhage, adenomas, fibroid degeneration, steatosis, foam cells, severe inflammatory cells with monocytic infiltration, edema, hemorrhage. Occluded, congested, and hypertrophied lung arteries in addition, degenerated thyroid follicles, were observed. The hyaline cartilage displayed degeneration, deformation, and abnormal protrusion. In conclusion, our results suggest that inhalation of very low concentrations of the gasoline additive MTBE could induce an increase in protein levels and resulted in histopathological alterations of the trachea and the lungs.

Localisation of basic fibroblast growth factor in cholesteatoma matrix: an immunochemical study.

OBJECTIVE: To investigate the expression of basic fibroblast growth factor in the matrix of human acquired cholesteatoma compared to the deep meatal skin. This topic does not appear to have been fully investigated before. METHODS: An immunochemical study was conducted. Cholesteatoma tissues from adult patients were collected during surgery (n = 19). Control specimens were taken from the deep meatal skin (n = 8) and compared. RESULTS: A highly significant difference in basic fibroblast growth factor expression was identified between cholesteatoma and skin (mean ± standard error = 58.53 ± 3.6 per cent in cholesteatoma vs 40.6 ± 3.5 per cent in skin; p = 0.005). Both basal and parabasal keratinocytes were stained positive with basic fibroblast growth factor. Additionally, there was specific staining in the basal columnar middle-ear epithelium and mast cell membrane. CONCLUSION: Basic fibroblast growth factor plays an active role in proliferative activity of cholesteatoma through its overexpression in basal and parabasal layers of cholesteatoma matrix. Moreover, its expression in the mast cell membrane supports its role in bone resorption activity.

Phenolics from Caesalpinia ferrea Mart.: antioxidant, cytotoxic and hypolipidemic activity.

Nine phenolics were isolated from the aqueous ethanol extract of the leaves of Caesalpinia ferrea. The isolates were characterized for the first time from that plant. The structures of all isolates (1-9) were elucidated by conventional methods, spectroscopic analysis, including 1 D and 2D NMR, and by HR-ESIMS as well. The antioxidant capacities using the ORAC method and the cytotoxic activity using the neutral red assay (NRU) for that extract and three major isolates have been evaluated. In addition, the hypolipidemic activity (in vitro and in vivo) of the extract has been assessed.

Bioassays guided isolation of compounds from Chaetomium globosum.

The aim of the present study was to evaluate different biological activities of the fungus Chaetomium globosum (family Chaetomiaceae). The evaluation was done through testing its antimicrobial, antioxidant and anticancer effects. C. globosum was isolated from the Cucumber soil (rhizosphere) and caused inhibition of the mycelial growth of Fusarium solani, Rhizoctonia solani and Sclerotium rolfsii in the biculture test. Petroleum ether and ethyl acetate extracts of the liquid culture of C. globosum showed potent in vitro antioxidant activity. C. globosum proved potent antibacterial activity against Bacillus subtilis, Escherichia coli and Pseudomonas fluorescens. It also recorded significant antifungal activity against Candida albicans, F. solani, Fusarium oxysporum, R. solani and Pythium ultimum. It exerted cytotoxic effect on human hepatocellular carcinoma cell line (HepG2). Unsaponifiable and saponifiable matters of the petroleum ether extract showed the presence of hydrocarbons, sterols and fatty acids. The ethyl acetate extract showed the presence of prenisatin, chrysophanol, chrysazin, chaetoviridin A and B. The isolated secondary metabolites proved significant antioxidant and antimicrobial activity on B. subtilis, E. coli and R. solani. In conclusion, this fungus showed different biological activities. Further studies must be done to apply its use in the agricultural and medicinal field.

Effects of black seed oil on resolution of hepato-renal toxicity induced bybromobenzene in rats.

OBJECTIVE: Volatile halocarbon, bromobenzene (BB), is frequently encountered in table-ready foods as contaminants residues. The objective of this study was to investigate whether black seed oil could attenuate hepato-renal injury induced by BB exposure. MATERIALS AND METHODS: The evaluation was done through measuring liver oxidative stress markers: reduced glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA). Hepatic succinate dehydrogenase (SDH), lactate dehydrogenases (LDH) and glucose-6-phosphatase (G-6-Pase) were estimated. Serum aspartate and alanine aminotransferases (AST, ALT) and alkaline phosphatase were also evaluated. Kidney function indices; blood urea nitrogen (BUN), creatinine, serum protein, nitric oxide (NO), Na-K-adenosine triphosphatase (Na+-K+-ATPase) and phospholipids were done. Liver and kidney histopathological analysis and collagen content were analyzed for results confirmation. RESULTS: Treatment with black seed oil (BSO) alleviated the elevation of GSH, SDH, LDH, G-6-Pase, serum protein, NO, Na+-K+-ATPase, phospholipids levels and attenuated MDA, SOD, AST, ALT and ALP. Diminution of collagen content and improvement in liver and kidney architectures were observed. CONCLUSIONS: BSO enhanced the hepato-renal protection mechanism, reduced disease complications and delayed its progression. Further studies are needed to identify the molecules responsible for its pharmacological effect.  

Malachite green induces genotoxic effect and biochemical disturbances in mice.

BACKGROUND AND OBJECTIVES: Malachite green (MG) is a triarylaminmethane dye used in the fish industry as an anti-fungal agent. Concern over MG is due to the potential for consumer exposure, suggestive evidence of tumor promotion in rodent liver, and suspicion of carcinogenicity based on structure-activity relationships. In order to evaluate the risks associated with exposure to MG, we examined the mutagenicity and biochemical effect of MG. MATERIALS AND METHODS: For genotoxic effect we use the doses 27, 91, 272 and 543 mg/kg b.wt. for different period of time (7, 14, 21 and 28 days) to evaluate chromosomal aberrations in mouse somatic and germ cells as well as sister chromatid exchanges in bone marrow cells. For DNA fragmentation assay from mouse liver the same doses of MG were used for 28 days. For measuring biochemical parameters such as glycolysis and gluconeogenesis enzyme pathways, antioxidant indices, hepatic marker enzymes, total protein, glucose, glycogen levels and liver function enzyme activities were evaluated. Mice were treated orally up to 28 days with the two high doses of MG 272 and 543 mg/kg b.wt. RESULTS AND CONCLUSIONS: Our results show that MG induce elevation in the percentage of SCE's and chromosomal aberrations (p < 0.01) after treatment with the high doses for long period of time. MG also induces DNA damage in mice liver in a dose dependent manner. Beside, MG treatment either in low or high doses causes biochemical disturbances in the major glucolytic-gluconeogenic pathways, hepatic marker enzymes, depleted glutathione and increased free radical as determined by increasing lipid peroxide. Histopathological observations revealed that MG induced sinusoidal, congestion, focal necrosis and degenerating in hepatic cells, hypertrophy and vacuolization followed by necrosis and cirrhosis.