Biochemical Changes Induced in Liver and Serum of Diplodiatoxin (Stenocarpella maydis) Treated Male and Female Rats

Abstract

Present study was conducted to investigate the acute and sub-acute toxic effect of diplodiatoxin with special reference to biochemical membrane bound enzymes like aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and RBC acetylcholinesterase (AChE) in male and female rats. For acute study, rats were treated with a single oral dose of 5.7 mg/kg of diplodiatoxin, whereas for sub-acute study, the rats received 0.27 mg/kg/day for 21 days. Acute and sub-acute diplodiatoxin treatment caused loss in body weight and feed intake along with symptoms including irritation, dullness, tremors and convulsions. Diplodiatoxin caused a significant increase in serum ASAT and ALAT and a decrease in activity in the liver in both acute and sub-acute studies. This compound also significantly inhibited RBC AChE. Sexual dimorphism was observed when male rats were compared with female rats (p<0.05). The enzyme alterations observed in the affected enzymes recovered to the normal levels by day 7 post treatment (withdrawal study) in both acute and sub-acute treated rats. A negative correlation was observed with regard to these enzymes when serum was compared with liver. These enzyme profiles show increases in serum with parallel decrease in liver, indicating necrosis of liver. These results suggest that diplodiatoxin has potential to affect hepatic end-points.     

The effect of chlorpromazine and carbamazepine on diagnostically relevant liver enzymes

No interactions related to the analytical method were observed between chlorpromazine (1) or carbamazepine (2) and activities of alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), glutamate dehydrogenase (GLDH) or lactate dehydrogenase (LDH). With respect to its cytotoxic potential 1 in cultures of isolated rat hepatocytes increased markedly the release of enzymes into the culture medium, whereas the overall activities of the enzymes were not influenced. 2 in cultured hepatocytes caused no significant effects on the activities of the enzymes investigated. Besides the investigation of methodically related interactions in pooled human serum the methodic procedure including the use of cultures of isolated hepatocytes allows to study also pharmacologically and toxicologically related interactions between drugs and diagnostically relevant liver enzymes.     

Effects of Vepacide (Azadirachta indica) on aspartate and alanine aminotransferase profiles in a subchronic study with rats

The aim of this study was to ascertain the long-term effects of Vepacide, a neem-based pesticide on biochemical profiles. Albino Wistar rats were treated orally with 80 (low), 160 (medium) and 320 mg/kg (high) doses of Vepacide in coconut oil for 90 days. Control rats received the same volume of the vehicle. Vepacide caused increase of aspartate and alanine aminotransferase in serum, kidney and lung, and these enzymes decreased in liver in both male and female rats when measured after 45 and 90 days of treatment. The two-way analysis of variance (ANOVA) showed that the alterations in these enzymes were dose- and time-dependent. Sexual dimorphism was observed when male rats were compared with female rats (Student t-test at P< 0.05). Positive correlation was observed with regard to these enzymes between serum, kidney and lung, whereas in the case of serum and liver, a negative correlation was recorded. These enzyme profiles elucidate that they increased in serum with simultaneous decrease in liver, indicating necrosis of liver, whereas in other tissues, the level of enzymes increased, showing an adaptive mechanism due to the chemical stress. The affected enzymes were recovered to normal conditions after 28 days of post-treatment (withdrawal study). Due to the Vepacide treatment, lung was more affected followed by liver and kidney. This study has indicated that these enzymes could be useful as biomarkers for the insult of any toxicant. Besides, they can also help in predictive toxicology.     

Trimetazidine ameliorates the hepatic injury associated with ischaemia-reperfusion in rats.

Ischaemia-reperfusion induces structural and functional damage to hepatocytes. The purpose of this study was to evaluate the protective effect of trimetazidine, an anti- ischaemic drug, in a rat liver model of ischaemia-reperfusion. Male Wistar rats were divided into groups pretreated with different doses of trimetazidine (1, 5, 10 or 20 mg kg-1 day-1) or saline for 7 days. Liver ischaemia was induced for 120 min and blood reflow was subsequently restored for 30, 60, 90 or 120 min. The activities of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) as well as the bile flow and the liver ATP content were determined. Ischaemia-reperfusion induced major alterations of hepatic functions involving increases of ASAT and ALAT activities, a drop of ATP content and a sharp decrease in bile flow. Trimetazidine pretreatment reduced the liver injury. Indeed, it lowered the increase in ALAT and ASAT activities observed immediately after reperfusion and maintained higher concentrations of hepatic ATP. Simultaneously, bile flow was increased. These effects were dose-dependent and 5 mg kg-1 day-1 seemed to be the lowest effective dose. In this experimental model trimetazidine pretreatment reduced the liver damage induced by ischaemia-reperfusion. Our data suggest that trimetazidine may be a useful drug in liver surgery to prevent ischaemia-reperfusion injury.     

Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran

Treatment of acute venous thromboembolism (VTE) and prophylaxis of recurrent events has been investigated in the THRIVE (THRombin Inhibitor in Venous Thrombe Embolism) Treatment and the THRIVE III trial using the oral direct thrombin inhibitor ximelagatran. Alanine aminotransferase (ALAT) increased in 9.6% and 6.4% of patients in the THRIVE Treatment and THRIVE III trials, respectively. The authors analysed the time course of the ALAT and in additionally of aspartate aminotransferase (ASAT) in blood from 52 and 23 patients participating in the THRIVE Treatment and the THRIVE III trials in Germany. Analysis of variance for repeated measures and t test were performed. In the THRIVE Treatment trial, ALAT was significantly higher at week 2 for enoxaparin/warfarin (p => .0039, t test) and at months 3 and 6 for ximelagatran (p = .0453, p = .0014, respectively). ASAT and ASAT/ALAT ratio values did not increase and not differ for both groups. In the THRIVE III trial, ALAT and ASAT did not increase and did not differ compared to the comparator placebo. 2 x 36 mg Ximelagatran, induced higher ALAT values at months 3 and 6 compared to 2 x 24 mg ximelagatran (p = .0105, p = .0063, respectively). ASAT did not differ between the two doses of ximelagatran. The ASAT/ALAT ratios were lower at week 2 for enoxaparin/warfarin (t-test, p = .0032) and at month 3 and 6 for 2 x 36 mg versus warfarin or 2 x 24 mg Ximelagatran (p between .0187 and .0002). The authors conclude that ALAT increases dose dependently during therapy with ximelagatran. The less frequent and lower increase of ASAT values compared to ALAT values indicates a nontoxic effect of ximelagatran on liver cells.     

Effect of Kalmegh extract on rat liver and serum enzymes

Oral administration of Kalmegh extract under acute (single dosage) and sub-acute (for 7 and 15 consecutive days) conditions at a dosage of 0.5 g dry leaf/kg/day to adult rats produced no change in the activities of glutamate oxaloacetic transaminase (GOT) and glutamate pyruvic transaminase (GPT) in liver and rerum. Administration of ethyl alcohol at a dosage of 0.2 g/kg/day (oral) for 7 and 15 consecutive days produced an appreciable increase in liver GOT and GPT activities. No appreciable change in serum GOT and GPT activities was observed under similar condition of treatment. Oral administration of a high dosage of ethyl alcohol (3 g/kg/day) produced significant increase in the activities of serum enzymes only. This alcohol-induced increase in serum transaminase activity became normal with pre- and post-treatment of Kalmegh extract (0.5 g/kg/day). This result suggests that Kalmegh extract protects alcohol-induced toxic-effect in liver tissue.     

Novel Sources of Mammalian C-S Lyase Activity

The C-S lysis of L-cysteine conjugates is one biotransformation pathway which is responsible for the generation of mutagenic and cytotoxic metabolic species. Thirteen cysteine S-conjugates were synthesized in our laboratories and incubated with aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) enzymes from porcine heart tissue. The C-S lyase (CSL) activity for each enzyme-substrate combination was determined. ASAT and ALAT were shown to exhibit CSL activity and it was also demonstrated that this activity was inhibited in the presence of the pyridoxal phosphate-dependent enzyme inhibitor amino(oxyacetic acid) confirming the pyridoxal phosphate-dependent mechanism by which C-S lysis is known to take place. This finding has potentially important implications for the risk assessment of compounds which produce L-cysteine conjugates during their biotransformation.     

Fumonisin B1-induced DNA damage in rat liver and spleen: effects of pretreatment with coenzyme Q10, L-carnitine, alpha-tocopherol and selenium.

Active oxygen radical species are reported to cause organ damage. This study was designed to determine whether oxidative stress contributed to the initiation or progression of hepatic and splenic cell DNA damage induced by fumonisin B1 (FB1) in rats. Another aim was to investigate the protective effects of the antioxidants coenzyme Q10 (CoQ10), L-carnitine, vitamin E (alpha-tocopherol) and selenium against DNA damage in the liver and spleen of rats treated with FB1. Fasted rats were injected intravenously with a single dose of fumonisin B1 at 1.55 mg kg-1 body wt. into the tail vein. Treatment with FB1 led to splenic and hepatic DNA fragmentation in 85% of the test animals. DNA fragmentation was investigated as a critical event in toxic cell death by testing total Ca2+ in liver. FB1 administration caused total Ca2+ in liver to increase within 4 h (204% of control). Measurement of liver enzyme activities showed an increase in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT). FB1 also markedly decreased splenic and hepatic glutathione (GSH) levels. Pretreatment with CoQ10 (30 mg CoQ10 kg-1 diet) together with L-carnitine (2.8 mg carnitine kg-1 diet), alpha-tocopherol (30 IU vitamin E kg-1 diet) and selenium (1 mg selenium as sodium selenite kg-1 diet), decreased DNA damage and the activities of Ca2+, ASAT and ALAT in the liver. On the other hand, the level of GSH was slightly increased. The CoQ10 alone did not significantly protect against toxic cell death and glutathione depletion caused by FB1. Oxidative damage caused by FB1 may be one of the underlining mechanisms of FB1-induced cell injury and DNA damage.     

Effect of S-adenosyl-L-methionine on thioacetamide-induced liver damage in rats

S-Adenosyl-L-methionine (Ado-met) administration to rats significantly improved liver necrosis induced by thioacetamide (TAA) as evidenced by reduction of TAA-elevated catalytic activity of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALAT). Ado-met, however, was not effective in reduction of catalytic activity of serum alkaline phosphatase (ALP) which increased as a consequence of TAA administration. Histologic analysis of the livers supported the biochemical data. Hepatocellular damage was evident from the first day of TAA treatment at daily (i.p.) doses of 50 mg/kg body wt. Maximal necrosis was apparent after 3 days of TAA administration. When rats were treated once a day, for 3 days with Ado-met (2 mg/kg body wt) as well as with TAA, significant reduction of hepatic necrotic area was observed. A similar effect was obtained when doses of 200 mg/kg body wt. of Ado-met were utilized.     

Early biochemical and histological changes in rats exposed to a single injection of thioacetamide

Liver injury was induced by one subcutaneous administration of thioacetamide (200 mg/kg b.wt.) and studied 24 and 48 hrs later. Levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) increased after 24 and 48 hrs. The lysosomal enzymes beta-hexosaminidase (beta-NAG) and beta-glucuronidase (beta-GLU) increased significantly after 24 hrs, while the level of beta-GLU returned to normal after 48 hrs, but the activity of beta-NAG remained significantly high even after 48 hrs. Histopathological examination showed necrotic hepatocytes around the central vein with infiltration of macrophages, neutrophils and eosinophils. The plasma zinc level decreased after 24 hrs and returned to normal after 48 hrs. Liver zinc content increased simultaneously at 24 hrs, returning to normal after 48 hrs. No alterations of plasma copper were observed after 24 and 48 hrs. Copper content of the liver increased significantly after 24 and 48 hrs. The present study thus shows that one dose of thioacetamide results in profound liver injury and supplementation of zinc prior to and simultaneously with thioacetamide normalized plasma zinc, increased liver zinc content and reduced the increase of beta-NAG, but did not influence the histological changes.     

Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals.

To determine the incidence of hepatotoxicity and to investigate whether plasma concentrations of nevirapine, in addition to other risk factors, could predict hepatotoxicity during treatment with nevirapine-containing regimens, we conducted a retrospective analysis with data from 174 individuals infected with human immunodeficiency virus-1 (HIV-1). During regular visits to the clinic, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters including liver enzymes (LEs) and total bilirubin (TBR). Severe hepatotoxicity was defined as a grade > or =3 elevation in at least one of the tested LEs or TBR levels while on therapy. Analysis of predictive factors was focused on increases in aspartate aminotransferase (ASAT) and/or alanine aminotransferase (ALAT) to grade > or =2. Grade > or =3 elevation developed with an incidence of 0.15 per patient year (PY); only 3.4% of the patients developed grade > or =3 values for ASAT and/or ALAT (incidence 0.03 per PY). We found that patients who use a protease inhibitor (PI) in a nevirapine-containing regimen and patients who have chronic hepatitis B (HBV) infection are at a higher risk for the development of increases in ASAT and/or ALAT to grade > or =2. In contrast, the plasma concentration of nevirapine does not appear to be a predictive factor in this study population.     

The effect of sub-acute and sub-chronic exposure of rats to the glyphosate-based herbicide Roundup

Roundup is a glyphosate-based herbicide that includes 78.5% glyphosate and surfactant at lower toxic concentrations. Glyphosate is an organophosphorated non-selective agrochemical widely used in many countries including Turkey and acts after the sprout in a systemic way. The objective of this study was to analyze toxic effects of the herbicide Roundup in rat liver. Animals were treated with 56mg/kg (p.o.) and 560mg/kg (p.o.) of Roundup (78% glyphosate+surfactant) each day, during 5 and 13 weeks. Hepatotoxicity was monitored by quantitative analysis of the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) activities and measured amount of serum lipoprotein (LDL, HDL), total cholesterol and creatinine were used as the biochemical markers of liver damages. Besides the biochemical analysis, we also investigated liver tissues histopathologically. Sub-chronic treatment, starting from the low and high doses of Roundup, it was observed that there were mild effects on activity of ALT, AST and LDH enzymes indicating the hepatic toxicity induced by Roundup. It was found that the mild effects were different on the enzymes in male and female rats of treatment groups. Also it was found some difference in serum lipoprotein (LDL, HDL) and t-cholesterol. There was no difference creatinine value between control and treatment groups but it was observed that degenerative formation such as mononuclear cell infiltration and congestion of the liver tissues of treatment groups.     

A 90 days oral toxicity of imidacloprid in female rats: Morphological,biochemical and histopathological evaluations

A 90 days oral toxicity study of imidacloprid was conducted in female rats with doses of 0, 5, 10, 20 mg/kg/day. Decrease in the body weight gain was observed at 20 mg/kg/day and at necropsy the relative body weights of liver, kidney and adrenal was also significantly increased at this dose level. No mortality occurred during treatment period while food intake was reduced at high dose level. In clinical chemistry parameters high dose of imidacloprid has caused significant elevation of serum GOT, GPT, glucose and BUN and decreased the activity of AChE in serum and brain. The spontaneous locomotor activity was also decreased at highest dose exposure where as there were no significant changes in hematological and urine parameters. The brain, liver and kidney of rats exposed with high dose of imidacloprid had showed mild pathological changes. Based on the morphological, biochemical, hematological and neuropathological studies it is evident that imidacloprid has not produced any significant effects at 5 and 10 mg/kg/day doses but induced toxicological effects at 20 mg/kg/day to female rats. Hence, 10 mg/kg/day dose may be considered as no observed effect level (NOEL) for female rats.     

Acid and alkaline phosphatase activities in a novel phosphorothionate (RPR-11) treated male and female rats. Evidence of dose and time-dependent response

The effect of a novel phosphorothionate, the methyl ester of 2-butenoic acid-3-diethoxy phosphinothioyl (RPR-II) was studied on membrane bound target enzymes Acid (AcP) and Alkaline (AkP) Phosphatases in different tissues of male and female albino Wistar rats. Three sub-chronic doses 0.014 (low), 0.028 (medium) and 0.042 (high)mg/kg-1 were administered to the rats daily for a period of 90 days. The long term and repeated administration of RPR-II caused significant increase of AcP and AkP in serum and kidney (AcP), whereas these enzymes simultaneously decreased significantly in liver, kidney (female rat AkP) and lung tissues in both male and female rats after 45 and 90 days of treatment. However, the kidney AcP increased significantly in both the sexes which is suggestive of an increase in synthesis of this enzyme which may be an adaptive mechanism to the toxicant stress. The changes in serum, liver, kidney and lung of both male and female rats by this compound were statistically significant when compared with two way Anova showing that they are dose and time dependent. The alterations in male rats were statistically insignificant when compared with female rats showing no sexual dimorphism by this compound. Recovery was observed after 28 days of post treatment (withdrawal study) indicating reversal of the toxic symptoms once the toxicant is removed. High degree negative correlation was observed for serum versus liver and lung and in other cases substantial correlation was observed. The changes observed in these enzymes showed that liver was most susceptible followed by lung and kidney. There are marker enzymes and their increase in different tissues might be due to the increased permeability of plasma membrane or cellular necrosis, showing the stress condition of the treated rats. This investigation elucidates the effect of these biomarker enzymes which increased in blood, might be due to the necrosis of liver, kidney and lung tissues by this compound.     

Toxicity profile of lisdexamfetamine dimesylate in three independent rat toxicology studies

Lisdexamfetamine dimesylate (LDX) is a d-amphetamine prodrug developed for the treatment of attention-deficit/hyperactivity disorder. The toxicity profile of orally administered LDX has been evaluated in rats. In an acute study, LDX doses of 60 mg/kg and higher caused increased motor activity. At 1000 mg/kg, one rat died and another was euthanized. In a 7-day repeat-dose study, all rats dosed with LDX (14 per dose group for each sex) showed increased activity; 10 male rats and 11 female rats at 300 mg/kg/day and 3 female rats at 100 mg/kg/day were euthanized because of self-mutilation and 1 male rat at 300 mg/kg/day was found dead. In a 28-day study, only rats at 80 mg/kg showed signs of self-mutilation and thin body condition. In both the 7- and 28-day studies, LDX caused significant changes in some blood chemistry parameters (e.g. blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase) and organ weights (e.g. particularly heart, liver, brain, and spleen). Overall, no apparent treatment-related histopathologic changes were observed. Toxicokinetic assessments indicated that as the dose of LDX was increased, rats were exposed to increasing levels of LDX and d-amphetamine. The extent of exposure to LDX and d-amphetamine increased after repeated-dose in the 28-day study. The findings of the repeat-dose studies indicate that the toxicity profile in rats administered LDX orally is comparable to that for d-amphetamine; however, the apparent lethal dose of LDX in rats is more than five times higher than the LD(50) of orally administered d-amphetamine, supporting a putative protective effect of conjugating amphetamine with lysine.     

Acute and Subacute Toxicity Studies of Erodium guttatum Extracts by Oral Administration in Rodents

The present study aimed to evaluate the acute and subacute toxicity profiles of Erodium guttatum extracts in mice using the methods described in the guidelines of the OECD. In the acute toxicity study, the LD₅₀ value was greater than 2000 mg/kg. The subacute toxicity study of E. guttatum extracts showed no significant changes in body or organ weights. The administration of E. guttatum extracts to mice at a dose of 200 mg/kg led to an increase in white blood cells, platelets and hemoglobin. Moreover, the aqueous extract of E. guttatum only decreased liver aspartate aminotransferase (ASAT) levels at a dose of 200 mg/kg, and creatinine and urea levels did not show any significant alterations compared to the control group. Our results showed that the extracts of E. guttatum caused a slight increase in alanine aminotransferase (ALAT) and triglycerides. The histological study showed that mice treated with E. guttatum extracts experienced some histopathological changes in the liver, particularly with the methanolic extract, and slight changes in the kidneys and pancreas. Regarding the renal profile, no toxicity was observed. These results provide basic information on the toxicological profile of E. guttatum used in traditional medicine.     

Acute and twenty-eight days repeated oral dose toxicity study of besifloxacin in Wistar albino rats

The purpose of this study was to investigate the potential acute and 28-day repeated oral toxicities of besifloxacin (BAF) in Wistar albino rats. In oral acute and repeated dose study, BAF was administered to both sex of rats, at dose levels of 0, 300, 600, 900 mg/kg/day and 0, 100, 200, 500 mg/kg/day, respectively. In the acute study, total white blood cell (WBC) (male, 43.74%; female, 42.60%) and total bilirubin (T-BIL) (male, 80%; female, 60%) were significantly increase, total protein (TP) (male, 23.24%; 27.80%) was significantly decreased, and significant incidence of pericholangitis (male, 83.33%; female, 75%) was shown in males and females of high-dose groups. In repeated oral dose toxicity study, similar type effects were also observed after serum hematological and serum biochemical analysis, whereas additionally sever hepatic injury and focal ulceration in gastric mucosa also observed in high dose groups of both sexes after histopathological analysis. However these toxic effects of besifloxacin were transient and reversible and no-observed adverse effect level (NOAEL) were 300 mg/kg/day for acute and 100 mg/kg/day for repeated dose toxicity study, respectively.     

Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols

We performed a uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study [enhanced Organization for Economic Co-operation and Development (OECD) test guideline No. 407] of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols. In the uterotrophic assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), the test chemical was orally administered to castrated male SD rats at doses of 0, 50, 200, and 1,000 mg/kg/day for ten consecutive days beginning on postnatal day 56, and no changes were observed. When this chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, an increase in thyroid weight was observed in the female rats in the 125 mg/kg group, an increase in serum thyroid-stimulating hormone (TSH) values in the male and female rats in the 125 mg/kg group, and a decrease in serum T3 and T4 values in the male rats in the 125 mg/kg group, and thyroid follicular epithelial cell hypertrophy was observed in some of the female rats in the 125 mg/kg group. These findings were concluded to be the result of endocrine-mediated effects of the chemical on thyroid function. In addition, increased liver weight, abnormal histological findings in the liver, and abnormal biochemical parameters related to liver function were observed in male and/or female rats in 5 mg/kg group and higher dose groups. The no-observed-effect level for 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) was concluded to be <5 mg/kg/day. In the uterotrophic assay of 3-(dibutylamino)phenol, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 3-(dibutylamino)phenol, the test chemical was orally administered at doses of 0, 50, 200, and 400 mg/kg/day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when this test chemical was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid weight increased in the male rats in the 300 mg/kg group, thyroid follicular epithelial cell hypertrophy was observed in a small number of male rats in the 300 mg/kg group, serum T3-values decreased in the female rats in the 300 mg/kg group, and a tendency for TSH-values to increase was observed in the male and female rats in the 300 mg/kg group. Therefore, 3-(dibutylamino)phenol was also concluded to have slight anti-thyroid acting effects as the endocrine-mediated effects. On the other hand, increased hemosiderin deposition in the spleen, increased spleen weight, hematological abnormalities, and squamous epithelial hyperplasia of the forestomach were detected in male and/or female rats in the 100 and/or 300 mg/kg groups, and thus the no-observed-effect level for 3-(dibutylamino)phenol was concluded to be 30 mg/kg/day.     

Effect of methomyl on hepatic mixed function oxidases in rats

Objective:

To study the effect of the methomyl on mixed function oxidase system in rats.

Materials and Methods:

The effect of the methomyl on mixed function oxidase was studied using different dosages, durations and sex. Microsomes were isolated using the calcium precipitation method. The levels of cytochrome P₄₅₀ , and cytochrome b₅ were determined using extinction coefficient of 91 and 85 mM^-1 respectively. The activities of drug metabolizing enzymes, hemoglobin content, liver function enzymes, and serum cholinesterase activity were assayed by using standard methods.

Results:

Intraperitoneal administration of methomyl (4 mg/kg body weight) showed significant decrease in the level of cytochrome P₄₅₀ , and the activities of aminopyrine N-demethylase and aniline hydroxylase on the third day of the treatment. Methomyl (4 mg/kg) treatment of old male rat and adult female rat also showed a decrease in the level of cytochrome P₄₅₀ , and aminopyrine N-demethylase activity. The serum samples from methomyl treated rats (male and female), when analyzed for alanine aminotransferase (SGPT) and aspartate aminotransferase (SGOT) as markers of the liver toxicity, showed significant increase in the activity. The activities of SGPT and SGOT were significantly higher in the treated rats (2 and 4 mg/kg) than in the control group. A significant decrease in the level of hemoglobin and serum cholinesterase activity was observed, when there was an increase in the dose level. A significant increase was observed in alkaline phosphatase activity at all dose levels.

Conclusion:

Methomyl influences mixed function oxidase and creates abnormality of liver functions in the rats. This effect depends on the dose and duration of methomyl.     

Depression of serum cholinesterase activity by cadmium

Two serum enzymes which originate from the liver under different circumstances were examined as potential biological indicators in serum for cadmium toxicity. The first of those is an enzyme that leaks from damaged liver cells. The second is an enzyme that is secreted by the normal functioning liver. Cadmium chloride was injected s.c. into male and female rats of the Wistar strain (8, 15 and 22 weeks old), at doses of 1.0, 1.5 and 2.0 mg Cd/kg body weight (in total 18 groups). Cholinesterase (CHE; EC 3.1.1.8) activity in serum was found to decrease with time after the administration of a single injection of cadmium chloride and, in all experimental groups, was significantly lower than the control values on day 2 after the injection. Glutamic pyruvic transaminase (GPT; EC 2.6.1.2) activity in serum, however, increased only in the oldest group of males receiving the high dose levels of cadmium. A time-course experiment in which male and female rats 15 weeks of age were administered 1.5 mg Cd/kg body weight showed that the serum CHE activity started to decrease on day 1 after the injection, attained the lowest level on days 2 and 3, and then recovered almost to control levels on day 5. On the other hand, the GPT activity remained at or less than control values throughout the experimental period. The results indicate that CHE activity in serum is a sensitive biological indicator for cadmium toxicity.