Influence of zinc chloride on the metabolism and hepatotoxicity of bromobenzene in rats

In studying the possible interactive effects of various heavy metals on bromobenzene hepatotoxicity and metabolism, zinc chloride (ZnCl2) (0.5, 2.0, and 10.0 mg/kg) was given ip 24 hr prior to ip administration of bromobenzene (2.5 mmol/kg body wt). Animals were sacrificed 48 hr after bromobenzene. A significant increase in the activities of serum transaminases (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) was observed at 0.5 mg/kg ZnCl2 and such an effect was not observed at the two higher doses of ZnCl2. However, no such increase in the transaminases activities was observed when rats were treated with identical doses of ZnCl2 48 hr before the administration of bromobenzene. When rats were treated with 2 mg/kg ZnCl2 6 hr prior to the bromobenzene dose, a potentiation of the hepatotoxicity due to bromobenzene was again observed, whereas simultaneous treatment of bromobenzene and ZnCl2 produced no such effect. Treatment with ZnCl2 (0.5 mg/kg) 24 hr prior to bromobenzene injection failed to modify the pattern of the urinary metabolites of bromobenzene. When rats were given 50, 250, or 500 ppm of ZnCl2 in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg bromobenzene, a reduction in the activities of serum transaminases was observed in 250 ppm ZnCl2-treated rats only. Such a reduction in the hepatotoxicity of bromobenzene is accompanied by a simultaneous reduction of the in vivo metabolism of bromobenzene by zinc, as substantiated by reduction of its urinary thioethers as well as of its total urinary metabolites. The present study has shown that changes in the metabolism and hepatotoxicity of bromobenzene depend on the dose of zinc administered, as well as on the temporal relationship between the zinc and bromobenzene administrations. The definitive mechanism responsible for such interactions remains to be elucidated.     

Influence of selenium on the metabolism of bromobenzene and a possible relationship to its hepatotoxicity

When male Sprague-Dawley rats were treated with sodium selenite (1 mg/kg, sc) 24 hr prior to or simultaneously with bromobenzene (2.5 mmol/kg, ip) and sacrificed 48 hr after the bromobenzene dose, increased levels of the activities of serum transaminases (serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) induced in the bromobenzene-treated rats were significantly reduced in the presence of selenium. However, no such reduction in the transaminases activities were observed when rats were either pretreated with selenite for 48 hr or pretreated with 0.1, 0.2, or 0.5 mg/kg of selenite. Although selenium alone had no effect on the hepatic microsomal drug metabolism, simultaneous treatment of selenite (1 mg/kg) with bromobenzene resulted only an increase in the activity of aniline hydroxylase after 48 hr as compared to that in the bromobenzene-treated group. When rats were given 2.5, 10, and 20 ppm of selenite in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg of bromobenzene and were sacrificed 48 hr after bromobenzene administration, a reduction in the SGOT activities in all the pretreated groups and a reduction of SGPT activity in 20 ppm selenite-treated group were observed when compared with those in the bromobenzene-treated groups. A dose-dependent increase in hepatic GSH concentrations were observed due to such chronic selenium treatment. Treatment with selenite (1 mg/kg) 24 hr prior to bromobenzene injection (2.5 mmol/kg) increased initially both o and p-bromophenols in the rat urine at 0-7.5 hr without affecting urinary thioethers. On the contrary, the ratio of thioethers to p-bromophenol was significantly higher in both 2.5 and 10 ppm selenite-pretreated (4 weeks) rats as well as a significant increase in the ratio of thioethers to total phenolic metabolites in 10 ppm and an increase close to significant in 2.5 ppm selenite-treated rats were observed initially at 0-7.5 hr urine samples. These results indicate that acute selenium pretreatment under certain conditions, favors increased hydroxylation of the intermediate bromobenzene epoxides, whereas higher detoxification of the epoxides involving hepatic glutathione (GSH)/GSH transferases pathway is more favored due to increased biosynthesis of GSH in certain chronic selenium treated rats.     

Collagen and elastin in the liver of rats intoxicated with mercuric chloride

Intoxication of rats with mercuric chloride (0.5 mg Hg/kg of body weight, daily for 10 weeks) increased the hepatic contents of soluble and insoluble collagen and elastin. The increase was associated with elevated serum aminotransferase and alkaline phosphatase activities, and decreased total protein level in serum. Inflammatory changes were found in the liver. An increase in the fibrous protein content suggests that inflammatory reaction to mercuric chloride can result in hepatic fibrosis.     

氯化汞对雄性大鼠生殖毒性的研究

目的探讨无机汞对雄性生殖系统的损伤机制.方法雄性Wistar大鼠随机分3组,分别隔日皮下注射剂量为1.0 mg/kg、3.0 mg/kg的HgCl2及生理盐水,连续21 d.观测睾丸及附睾脏器系数、生精细胞凋亡情况、脂质过氧化物(LPO)、一氧化氮(NO)含量以及染毒前后血清睾酮水平.结果(1)3.0 mg/kg HgCl2染毒组大鼠睾丸及附睾脏器系数分别为0.74、0 26,均低于对照组(睾丸0 89,附睾0.30),差异有显著性(P＜0.05).(2)1.0 mg/kg及3.0 mg/kg HgCl2染毒组染毒后睾酮水平分别为0 93、0 69 nmol/L,均低于染毒前(5.01、3.02 nmol/L)及对照组(5 49 nmol/L),差异有显著性(P＜0.05).(3)1.0 mg/kg和3 0 mg/kg HgCl2染毒组LPO分别为17.34、21.59 μmol/ml;NO分别为62 91、73.09μmol/ml,均高于对照组(LPO 10.32 μmol/ml,NO 49 86μmol/ml),差异有显著性(P＜0.05).(4)3 mg/kg HgCl2染毒组平均曲细精管面积为56 159.01μm2/个,低于对照组(1 222 274.39μm2/个),差异有显著性(P＜0.05).1.0 mg/kg HgCl2染毒组平均每个曲细精管的凋亡细胞数为114.20个,高于对照组(39 02个),差异有显著性(P＜0.05).1、3.0 mg/kg HgCl2染毒组单位曲细精管面积内凋亡细胞数分别为1 06×10-3个/μm2、1.04 × 10-3个/μm2,均高于对照组(0.33个),差异有显著性(P＜0.05).结论HgCl2可诱发大鼠生精细胞凋亡,可能是对雄激素缺失信号的应答;睾丸组织处于氧化应激状态和生精细胞凋亡增加、睾酮水平下降可能有一定关系.     

五味子乙素对汞性大鼠急性肾损伤的影响

目的探讨五味子乙素(Sch B)对汞致大鼠急性肾损伤的影响。方法 Wistar大鼠30只,按体重随机分成5组:第1组为正常对照组,第2~4组分别为低、中、高剂量单纯染汞组,第5组为Sch B预处理组。对照组和单纯染汞组空腹以大豆油灌胃,Sch B预处理组16 mg/kg Sch B空腹灌胃,灌胃容量为5 ml/kg;2 h后,对照组皮下注射生理盐水,低、中、高剂量单纯染汞组分别皮下注射2.2μmol/kg、4.4μmol/kg、8.8μmol/kg氯化汞,Sch B预处理组皮下注射8.8μmol/kg氯化汞,注射容量为5 ml/kg。第二日重复上述操作,并将大鼠放入代谢笼,收集24 h尿液;而后将大鼠乙醚麻醉,腹主动脉采血,切取大鼠肾皮质,测定尿汞和肾皮质汞,尿β-N-乙酰氨基葡萄糖苷酶(NAG)、尿乳酸脱氢酶(LDH)及尿碱性磷酸酶(ALP)活力,尿蛋白和血尿素氮(BUN)含量,肾皮质还原型谷胱甘肽(GSH)和丙二醛(MDA)含量,超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活力。结果与对照组比较,高剂量氯化汞组尿汞和肾皮质汞含量,尿NAG、LDH及ALP活力,尿蛋白和BUN含量,GSH和M...     

Binding of mercury by chromatin of rats exposed to mercuric chloride

The extent of mercury binding by the chromatin of kidneys and liver of rats exposed to²⁰³HgCl₂ (20 mg Hg/kg body wt; single intravenous injection) was investigated. A considerable accumulation of this metal into cell nuclei of both the examined organs was observed (1.9 and 0.1 μg Hg/mg protein, respectively). Even higher mercury content was recorded in the chromatin preparations. The nonhistone chromatin proteins (NHP) were mainly responsible for deposition of mercury in the chromatin. One mg of these proteins contained 5.2 and 0.6 μg Hg for the kidneys and liver. Mercury bound to NHP constituted about 50% of the metal retained in the cell nuclei and 78–85% of mercury contained in the chromatin. As indicated by SDS—polyacrylamide gel electrophoresis the mercury-binding nonhistone proteins are heterogenous.     

Mechanisms for modification of bromobenzene hepatotoxicity by coadministered toluene and chlorobenzene

Hepatotoxicity of bromobenzene (2 mmole/kg) in combination with toluene or chlorobenzene (4 mmole/kg each) were studied in vivo on the basis of GPT elevation and histological examinations. Both toluene and chlorobenzene suppressed bromobenzene hepatotoxicity 24 hr after the treatment, and chlorobenzene dramatically potentiated the toxicity at 48 hr. The glutathione level became lower at 12 hr and recovered at 24 hr when bromobenzene was given alone. The recovery delayed until 48 hr when chlorobenzene was coadministered. In experiments in vitro with microsomes from phenobarbital-pretreated rats, both toluene and chlorobenzene at 0.6 mM inhibited p-bromophenol formation noncompetitively but had no effect on o-isomer formation. Multiple factors may determine overall hepatotoxicity in combined exposure; bromobenzene hepatotoxicity will be suppressed in the early phase owing to metabolic inhibition of 3,4-epoxidation, but potentiated later because of delayed recovery in the glutathione level. A time-saving yet reliable assay system with an ECD-gas chromatograph was developed for bromobenzene metabolism study.     

Dose-dependent metabolism of trichloroethylene and its relevance to hepatotoxicity in rats

Fasted male Sprague-Dawley rats pretreated with phenobarbital received an intraperitoneal injection of 0.00, 0.25, 0.50, 0.75, 1.00, 1.50, or 2.00 ml/kg of trichloroethylene (TRI) in corn oil. The metabolic fate of TRI was monitored by measuring its major urinary metabolites 24 hr following the dosing. The hepatotoxic response of TRI was evaluated by determination of the serum transaminase activities (SGOT and SGPT) 24 hr after dosing. Treatment of rats with TRI up to 0.5 ml/kg did not affect the transaminase responses, but significant response was manifested at 0.75 ml/kg dose. Further continuous increases in such responses were induced on exposure to higher doses. Dose-dependent urinary excretions of trichloroethanol and trichloroacetic acid were observed and reached an apparent saturation at 1-1.5 ml/kg dose of TRI. The percentage of dose excreted as trichloroethanol was decreased from 16% at 0.25 ml or 2.8 mmole/kg to 8% at 2 ml or 22.3 mmole/kg dose. The percentage of trichloroacetic acid was decreased from 5 to 2% for the same dose interval. A maximum of only 29% depletion of hepatic glutathione was observed at 2 hr following 1 ml/kg dose of TRI. Similarly, the excretion of urinary mercapturic acid of TRI or thioether was insignificant at any dose level. These results suggest that the conjugation of hepatic glutathione with the electrophilic intermediate of TRI does not seem to be an important determinant for TRI hepatotoxicity nor the major detoxification pathway of its reactive intermediate. TRI produced also a dose-dependent decrease in hepatic microsomal monooxygenase activities as well as cytochrome P-450 content. All these results, when combined, show that there exists an apparent saturable metabolism of TRI involving its activation/deactivation pathways which correspond to an apparent threshold or minimal toxic dose, about 1 ml/kg or 11.15 mmole/kg of TRI for its hepatotoxicity.     

Lead reduces the nephrotoxicity of mercuric chloride

The nephrotoxic effect of a single intraperitoneal dose of mercuric chloride (HgCl(2); 6 mg/kg) on adult CD-1 female mice was reduced at 24 and 48 h after injection, by a 48-h pretreatment nontoxic dose of lead acetate (Pb; 5 mg/kg) delivered by intravenous tail-vein injection (intravenous). While protection is temporally associated with lead-induced mitosis, occurring about 39 h after intracardiac lead injection (D. D Choie and G. W. Richter, 1974, Lab. Invest. 30, 447-451), the mechanism of the observed protection remains to be established.     

Effect of mercuric chloride on phospholipid peroxidation in rat

Individual molecular species of mercuric chloride induced phospholipid peroxide formed in rat brain, liver and kidney were determined using the multi-channel UV-high-performance liquid chromatography (HPLC) combined with potentiometric determination. Mercuric chloride (0.5 mg/kg/day) was administered subcutaneously to rats for 3 days. In accordance with a specified time schedule following administration (0.5, 1, 3 and 5 days), rats were decapitated and the phospholipids of brains, livers and kidneys were extracted and purified. The samples were then injected into the HPLC and the ratio (235 nm/203 nm) of peak area of each phospholipid was calculated. The peroxide value of each sample was determined using the calibration curve of the auto-oxidized standard phospholipids which were analyzed by both potentiometric determination and UV HPLC. Kidney phospholipid peroxides were easier induced than those in other organs reached their maximum peak (20.5 meq./kg) at 1 day after initial administration. Phospholipid peroxides in kidney and brain showed similar movement, while those in liver showed their maximum peak 3 days later. Of the phospholipids, phosphatidylserine and phosphatidylethanolamine seemed to be more susceptible to lipid peroxidation induced by mercuric chloride, the common feature of these two phospholipids being that both of them have primary amine group(s) on their polary heads and both are located on the cytosolic side of cell membrane. These results may be explained by mechanisms that relate to the interaction between mercurials and cell membranes or that between mercurials and primary amine groups of phospholipids. Further study is necessary to clarify the specific mechanisms involved in the induction of lipid peroxidation by mercurials and the interaction of mercurials with phospholipids.     

Influence of N-acetylcysteine against dimethylnitrosamine induced hepatotoxicity in rats

This study evaluates the hepatoprotective and antioxidant properties of N-acetylcysteine (NAC) on dimethylnitrosamine (DMN) induced hepatotoxicity in male Wistar albino rats. A single intraperitoneal dose of DMN (5 mg/kg b.w.) caused a significant increase in the levels of the serum marker enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamyl transpeptidase (γ-GT)) and a subsequent decrease in AST, ALT, ALP and increase in LDH and γ-GT in the liver tissue indicating hepatocellular damage. Elevation in the status of lipid peroxidation, fall in the activities of the enzymic (superoxide dismutase, catalase) and non-enzymic antioxidants (vitamin C, vitamin E) in the liver tissue further confirms oxidative stress and hepatocellular damage induced on DMN administration. Oral administration of NAC (50 mg/kg b.w.) for 7 days significantly prevented the above alterations in the status of the marker enzymes of hepatotoxicity and antioxidant parameters and restored them towards normalcy, which was further substantiated by the histopathological studies of the liver tissue. These results suggest that NAC offers hepatoprotection by ameliorating DMN-induced oxidative stress and hepatotoxicity and this protective effect was attributed to its antioxidant and free radical scavenging properties.     

The influence of age on the gastrointestinal absorption of mercuric chloride and methyl mercury chloride in the rat

The intestinal absorption of mercuric chloride and methyl mercury chloride was determined in neonatal (6-day-old) and mature (7-week-old) rats. No differences between the two age groups were observed in the absorption of methyl mercury chloride (0.08 μg Hg/ml) determined up to 2 hr after administration in vivo into closed segments of the duodenum or ileum. In contrast, the 1-hr duodenal absorption of mercuric chloride (8 μg Hg/ml) was significantly greater in neonatal animals (18.1%) as compared to 23-day-old weanling (7.3%) or mature (3.6%) animals. Ileal absorption of mercuric chloride was also higher in neonates than in mature animals, but the magnitude of the difference was less than that observed in the duodenum. GI absorption of mercuric chloride (46 μg Hg/kg) was also assessed in neonatal, weanling, and mature rats at 4 and 43 hr after gastric intubation. The percentage of the dose in the carcass, determined after removal of the GI tract, was significantly higher at both times in neonatal and weanling rats as compared to mature animals. Analysis of mercury content in the gastrointestinal tract of these animals also indicated age-dependent differences in mercury transit through the GI lumen. The extent of gastric emptying of mercury by 4 hr after dosing was significantly less in neonatal and weanling rats compared to mature animals. In addition, the small intestinal transit of mercury was markedly slower in neonates with 74.8% of the dose in the GI tract after 43 hr as compared to 5.2% and 3.0% in weanling and mature animals, respectively. These findings indicate that in the neonate, exposure to inorganic mercury by the oral route can be expected to result in higher systemic, as well as small intestinal, levels of mercury because of enhanced GI absorption and decreased luminal transit, respectively.     

Effect of chronic mercuric chloride poisoning on the levels of connective tissue metabolites in the urine and blood of rats]

Mercury chloride was administered into rats (1 mg/kg) in drinking water daily for 12 weeks. Revealed was an increase in the content of oxyproline and glycosaminglycanes in urine, as well as increased concentration of these compounds in blood serum. Glycosamine growth was accompanied by decreased contents of keratin sulphates and higher concentrations of heparin and heparin sulphates. The results indicated to the influence of mercury on the connective tissue metabolism.     

Effect of mercuric chloride on the analysis of nitrites in pork products

The effect of HgCl2 on nitrite determination was studied. 0,184 mmol/l to 184 mmol/l Hg Cl2 were added during the defecation or only at the time of analysis with an autoanalyser. Hg Cl2 was added to salami, bacon, dry sausage at different time of ripening and cooked ham. An effect was noted only when Hg Cl2 was added at the defecation time. After cold water extraction, the more the added Hg Cl2, the more "titrated" nitrite. After hot extraction with water and borate, the effect of Hg Cl2 was weaker but significant. The role of Hg Cl2 was important for the accurate determination of nitrites during the ripening of some products: in 16 hours old dry sausage the effect was weak (+40%), but became large (+600%) after 2 weeks of ripening. It is proposed to use Hg Cl2 at the concentration of 4 mmol/l for the determination of total nitrites. The free nitrites should be analysed separately without Hg Cl2.