Changes in concentration of essential metals in kidneys and urine as indices of gentamicin nephrotoxicity in female Wistar rats.

Wistar rats were treated with gentamicin in single (80 mg/kg) or repeated doses (7 x 40 mg/kg) subcutaneously. Total protein as well as excretion of essential metals (Cu, Zn) with the urine were determined 24 hr after 1, 3 and 7 dosages as well as 3 and 7 days after the termination of administration. At the same time kidneys were examined histopathologically by light microscopy. Simultaneously, Cu, Zn and metallothionein levels in kidneys and liver were determined. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis at the end of 7 days administration. At the same time elevated copper and zinc levels were observed in urine. These essential metals seem to be an indicator of gentamicin nephrotoxicity.

Dynamics of glutathione levels in liver and indicatory enzymes in serum in acetaminophen intoxication in mice.

Acetaminophen (AA) was administered i.p. to Swiss mice as a single dose 100, 200, 300, 400 and 600 mg/kg. At different time periods after administration, the mice were sacrificed. Serum glutamate-pyruvate transaminase (SGPT) and sorbitol dehydrogenase (SDH) as well as glutathione (GSH) levels in the liver were determined. It was found that the effective dose ranged within 200-600 mg/kg. Changes in GSH level occurred shortly after acetaminophen administration, whereas changes in the activity of indicatory enzymes were slightly delayed compared to this process. Conditions allowing for parallel observations of all three indices under investigation occurred 4 hrs after acetaminophen administration. With regard to glutathione, directly measured decrease, as compared to control levels, may be used as the yardstick of the changes. Changes in the activity of indicatory enzymes may be better expressed in the dose-response arrangement. For all the indices determined 4 hrs after acetaminophen administration, ED50 is in the range 200-300 mg/kg.

Induction of hepatic metallothionein following administration of urethane.

Induction of hepatic metallothionein (MT) by urethane (ethyl carbamate) was characterized. Male CF-1 mice were treated with urethane (0, 0.5, 1.0, 1.5, and 2 g/kg; ip) and 18 hr later hepatic MT concentrations were determined with the Cd-hemoglobin radioassay. Urethane (1 g/kg and higher) significantly increased hepatic MT levels, resulting in a 14-fold increase after 2 g/kg. Time-course experiments indicated that MT levels were increased significantly at 6 hr after administration of urethane (1.5 g/kg) and reached a maximum between 12 and 24 hr. Gel filtration, anion-exchange chromatography, and ultraviolet spectral analysis were used to characterize the protein induced by urethane. Pretreatment with actinomycin-D prevented induction of MT by urethane. Administration of equimolar dosages (20 mmol/kg) of urethane, N-hydroxyurethane, and methyl carbamate indicated that urethane and N-hydroxyurethane induce MT but that methyl carbamate does not. MT induction was also not observed with other commonly used anesthetics (pentobarbital and phenobarbital). In conclusion, urethane induces hepatic MT but this effect is not related to its anesthetic action, nor is it a common property of all carbamates.

Comparison of the effects of sodium sulfate and N-acetylcysteine on the hepatotoxicity of acetaminophen in mice.

N-acetylcysteine (NAC) has been proposed to decrease the toxicity of acetaminophen (AA) via two mechanisms: by increasing cysteine availability for hepatic glutathione biosynthesis and by increasing inorganic sulfate levels, which would increase AA sulfation and elimination. Because administration of sodium sulfate also reportedly decreases AA-induced toxicity, we have investigated the role of inorganic sulfate in the antidotal properties of NAC. Simultaneous administration of NAC (4 mmol/kg) and AA (2.5 and 4 mmol/kg) to male mice prevented AA-induced lethality and hepatotoxicity whereas sodium sulfate (4 mmol/kg) did not. Neither NAC nor sodium sulfate produced significant changes in the half-life (44 min) or clearance (9.0 ml/min/kg) of AA (4.0 mmol/kg) from blood nor were the amounts of AA-sulfate, AA-cysteine or AA-mercapturate excreted in urine altered. Injection of either sodium sulfate or NAC increased serum sulfate concentration and prevented the depletion in serum sulfate produced by AA. Hepatic adenosine 3'-phosphate 5'-phosphosulfate concentrations were decreased 15 and 30 min after AA and injection of either sodium sulfate or NAC lessened this effect. The concentration of glutathione in liver was decreased markedly after AA. NAC attenuated this effect but sodium sulfate did not. Sodium sulfate did not decrease covalent binding of tritium derived from [3H]AA to liver protein whereas NAC decreased binding by 25%. These findings show that administration of sodium sulfate increases serum sulfate concentration and hepatic adenosine 3'-phosphate 5'-phosphosulfate levels but does not protect against acetaminophen-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

The tissue disposition of zinc and copper following repeated administration of cadmium and selenium to rats.

Female rats were divided into four groups of five rats each including one control group (C). The animals were administered Na2SeO3 (Se), (CdCl2 Cd), and Na2SeO3 + CdCl2 (Cd + Se). Sodium selenite was given intragastrically at a dose of 0.5 mg Se/kg every day and cadmium chloride was injected subcutaneously every other day at a dose of 0.3 mg Cd/kg for 2 weeks. Exposure of rats to Cd caused an increase in the concentration of copper in the kidneys, blood, and liver and a decrease in the lung, but increased the concentration of zinc in the liver and brain and diminished it in the muscles and bones. In animals exposed to Se an increase in the copper concentration was observed in blood and brain; zinc was increased in the blood, heart, brain, and stomach, but decreased in the kidneys. Exposure of rats to Cd + Se resulted in an increase of copper in the kidneys and a decrease in the spleen, lungs, stomach, muscles and bones. Se prevented the cadmium-induced diminution of the zinc levels in the muscles and bones.

Interaction of alkylmercuric compounds with sodium selenite. III. Biotransformation, levels of metallothioneinlike proteins and endogenous copper in some tissues of rats exposed to methyl or ethylmercuric chloride with and without sodium selenite.

The biotransformation efficiency of alkylmercurial compounds was studied in rat liver, kidneys, blood, and brain after 2-week administration of methylmercuric chloride (MeHg) and ethylmercuric chloride (EtHg) at doses of 0.25 or 2.5 mg Hg/kg, alone or in combination with sodium selenite (Se) at a level of 0.5 mg Se/kg. Simultaneously, the level of metallothioneinlike proteins (MTP) and endogenous copper (Cu) was monitored in tissues of control rats and intoxicated rats. Regardless of the dose, the highest concentrations of inorganic mercury from both the alkylmercurials was found in the rat kidneys. Sodium selenite had a variable effect on the amount of inorganic mercury liberated, depending on the organ and the molar ratio of Hg:Se administered. A statistically significant increase in the levels of MTP and endogenous Cu, compared with control group, was found only in the kidneys of intoxicated rats. This increase was dependent on the concentration of inorganic mercury liberated by biotransformation of alkylmercurials. The observed changes appeared when the level of inorganic mercury exceeded 10 micrograms Hg/g tissue and reached a plateau at about 40 micrograms Hg/g tissue. In the presence of selenium the plateau of MTP and Cu levels were no observed in the kidneys, regardless of the amount of inorganic mercury liberated.

Interaction of alkylmercuric compounds with sodium selenite. II. Metabolism of methylmercuric chloride administered alone and in combination with sodium selenite in rats.

Repeated doses of sodium selenite (Se) were administered to rats receiving repeated (IV or PO) doses of 0.25 or 2.5 mg Hg/kg methylmercuric chloride (Me2(203)Hg). Se (0.5 mg/kg) was observed to alter the distribution of Me203Hg among tissues as well as among subcellular fractions of kidneys and liver. An excess of selenium resulted in a twofold decrease in the mercury content of kidneys and a similar increase in the mercury content of brain.

Activity of chosen indicator enzymes in blood serum of guinea pigs exposed to ethyl- and phenylmercuric chloride alone or jointly with sodium selenite.

The effect of sodium selenite on the activity of the selected enzymes in blood serum and on mercury concentration in some tissues of guinea pigs exposed to ethyl- (EtHg) or phenylmercuric chloride (PhHg) was investigated. Every second day for a 3-month period animals were given intragastrically a solution of mercuric compounds (2.5 mg Hg/kg) with or without sodium selenite (1 mg Se/kg). The activity of malate dehydrogenase (MDH, EC 1.1.1.37), phosphohexoizomerase (PHI, EC 5.3.1.9), and gamma-glutamyltranspeptidase (GGTP, EC 2.3.2.2) in blood serum of control animals was ca. 3.8, 325, and 48 IU. After 10 weeks of exposure to EtHg and PhHg, the activities (IU) of the above enzymes were, respectively, 5.9 and 6.5 (MDH), 585 and 600 (PHI) and 211 and 86.5 (GGTP). Sodium selenite administered with mercuric compounds did not prevent in increases in enzyme activity. During the experiment the level of inorganic as well as organic mercury accumulated in kidneys and liver was estimated. After a 12-week exposure, sodium selenite decreased the level of total mercury in the liver (in the case of both EtHg and PhHg: from 47.0 to 31.8 and from 41.3 to 25.4 micrograms Hg/g tissue, respectively). It also slightly decreased the mercury level in the kidneys of animals exposed to PhHg (from 889 to 73.3 micrograms Hg/g tissue) but did not change the mercury concentration in the kidneys of guinea pigs exposed to ethylmercuric chloride.

Interaction of alkylmercuric compounds with sodium selenite. I. Metabolism of ethylmercuric chloride administered alone and in combination with sodium selenite in rats.

The effect of sodium selenite administered intragastrically in repeated doses to rats receiving ethylmercuric chloride po in various repeated doses (0.25 or 2.5 mg Hg/kg) on the excretion, whole-body retention, and organ distribution of mercury was studied. Selenium was found to affect the distribution of ethylmercury among tissues and subcellular fractions of the kidneys and liver as well as its binding to proteins of soluble fractions in these organs. Similarities and differences between the effect of interaction of sodium selenite with ethylmercuric chloride and methylmercury as well as inorganic mercury are also discussed.

The influence of selenium on the level of mercury and metallothionein in rat kidneys in prolonged exposure to different mercury compounds.

Mercuric chloride, phenylmercuric chloride, ethylmercuric chloride /0,23 mg Hg/kg/ and methylmercurycyan guanidine /0,46 mg Hg/kg/ were orally administered to rats every second day for 14 weeks. The same doses of the above mentioned mercury compounds were administered alternately with sodium selenite /0,18 mg Se/kg/ to parallel groups of rats at the same time. The level of total and inorganic mercury and of metallothionein was determined. All mercury compounds increased the level of metallothionein in rat kidneys. In rats which received only selenium the level of metallothionein was twice lower in the kidneys in relation to the physiological level of this protein. Selenium eliminated the stimulation of biosynthesis of metallothionein by mercury.