Reconsideration of some hypotheses on the mechanism of thallium toxicity in rats with special respect to riboflavin and glutathione.
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Animals↗
Biomedical subjects
D Appenroth
Publications and source records attributed to D Appenroth.
Vitamin E and C in the prevention of metal nephrotoxicity in developing rats.
The protective effect of vitamin E and C on sodium chromate (Cr) and thallium (Tl) induced nephrotoxicity was tested in 10- and 55-day-old rats. The concentrations of Cr and Tl were determined in renal cortex and medulla by atomic absorption spectrometry. Urinary volume and protein excretion as well as blood urea nitrogen (BUN) concentration were determined as parameters of nephrotoxicity. Cr and Tl induced nephrotoxicity was significantly more expressed in adult than in young rats. In Cr and Tl nephrotoxicity the protective effect of vitamin E was evident in both age groups. Vitamin E decreased Tl concentration in renal tissue. Therefore its protective effect is not to be attributed to its known antioxidant effect but to lower Tl concentration in renal tissue. Vitamin C was protective in Cr and Tl induced nephrotoxicity in adult rats without influence on metal concentrations in renal tissue. The dose necessary for protection against toxic Cr action in adult rats was not tolerated by young rats. The combined administration of both vitamins abolished the protective effect against Cr nephrotoxicity of the administration of each vitamin alone in adult rats. When vitamin E and C were administered in Tl treated adult and young rats the protective effect was the same as after the administration of each vitamin alone. Possible mechanisms are discussed.
Animals↗
Protective effects of vitamin E and C on cisplatin nephrotoxicity in developing rats.
The kinetics of vitamin E was followed in serum, liver and kidney of 10- and 55-day-old rats after the administration of a single i.m. dose of 100 mg alpha-tocopherol acetate/100 g body wt. The basal levels without vitamin E administration were significantly higher in serum and liver of 10- than 55-day-old rats. The effect of vitamin E on cisplatin (CP; 0.6 mg/100 g body wt., i.p.) nephrotoxicity was investigated by determining urinary volume and protein excretion, as well as the concentration of blood urea nitrogen (BUN) and lipid peroxides in renal tissue (LPO). Previously described age differences in CP nephrotoxicity were confirmed. The administration of vitamin E, 12 h prior to CP, diminished the toxic effect of CP in young and adult rats. This effect could not be enhanced by a second administration of vitamin E. The simultaneous administration of vitamin E and C 12 h prior to CP intensified the protective effect of a single administration of vitamin E in 10- and 55-day-old rats without influencing the concentration of platinum in renal tissue.
Aging↗
Renal amino acid transport in immature and adult rats during thallium-induced nephrotoxicity.
The effect of Tl2SO4 (Tl, 2 mg/100 g b.wt.) on renal amino acid excretion and plasma amino acid composition was investigated in 10- and 55-day-old rats. Tl decreased glomerular filtration rate only in adult rats. On the other hand, the renal fractional excretion (FE) of amino acids was distinctly higher in adult rats as a sign of lower amino acid reabsorption capacity after Tl. In immature animals FE was increased only for a few amino acids. However, in both age groups Tl administration significantly decreased plasma amino acid concentrations, and was more pronounced in immature rats. The investigation of renal amino acid handling (1) confirms that Tl was more nephrotoxic in 55-day-old animals as demonstrated before using other parameters for nephrotoxicity testing and (2) showed that determination of renal amino acid handling is a suitable marker for nephrotoxicity in adult rats.
Aging↗
Contribution to the mechanism of chromate nephrotoxicity in developing rats: EPR investigations.
The effect of 2 mg and 1 mg Na2Cr2O7 (Cr)/100 g body wt. on renal function was investigated in 10- and 55-day-old rats, respectively. These doses were followed by equal Cr concentrations in the renal tissue of both age groups. Confirming previous data we found lower nephrotoxicity in young than in adult rats. The concentration of glutathione (GSH) and the activity of glutathione reductase (GSSG reductase) in renal tissue of adult rats were diminished by buthionine sulfoximine (BSO) and lomustine (CCNU) administration, respectively. In these animals Cr nephrotoxicity was decreased significantly. Lower nephrotoxicity was accompanied by slower disappearance of Cr(VI) from renal tissue homogenate in vitro. The time course of Cr(VI) reduction demonstrated by the signal intensity of Cr(V), as recorded by electron spin resonance (EPR) spectroscopy in the supernatant of renal tissue homogenate, enabled us to follow the reduction of Cr(VI) to Cr(III) via Cr(V). Maximally reached Cr(V) concentrations lowest in young rats, did not differ significantly in adult control and BSO and BSO + CCNU treated rats. Further reduction of Cr(V) to Cr(III) which appeared most rapidly in adult rats, was delayed by pretreatment with BSO and CCNU. From our results we concluded that (1) reduction of Cr(VI) was more related to the concentration of GSH than to the activity of GSSG reductase, (2) the formation of Cr-GSH-complexes with GSH oxidation seemed to be the first step of Cr(VI) metabolism, and (3) the stabilization of reactive Cr(V) by GSH seemed to be decisive for the preventive effect of BSO and CCNU as well as for age differences in chromate nephrotoxicity.
Age Factors↗
Riboflavin can decrease the nephrotoxic effect of chromate in young and adult rats.
The influence of 5 mg vitamin B2/100 g b.wt. (B2, riboflavin) on the nephrotoxic effect of 1 or 2 mg Na2Cr2O7/100 g b.wt. (Cr) was investigated in 55- and 10-day-old rats, respectively. Nephrotoxic effect was evaluated by the determination of urinary volume and protein excretion as well as the concentration of blood urea nitrogen (BUN). The concomitant administration of Cr and B2 only in 55-day-old rats increased the nephrotoxicity shown by enhanced proteinuria and BUN. B2, administered 3 h after Cr, was able to diminish Cr nephrotoxicity significantly in 55- and 10-day-old rats. The effect of B2 on Cr nephrotoxicity could be interpreted not by the stimulatory effect of B2 on GSSG reductase, which was abolished by Cr; but by its antioxidant effect.
Age Factors↗
Functional and morphological aspects of thallium-induced nephrotoxicity in rats.
Until now the effect of thallium (Tl) on renal function has not been investigated systematically. Therefore, the dose (5, 10, 15, 20 mg Tl2SO4/kg body wt., intraperitoneally) and time-dependence of renal damage was investigated in diuresis experiments on conscious rats. Morphology was evaluated after perfusion fixation in situ. Morphologic changes were localized in the thick ascending limb of the loop of Henle, mostly expressed at the 2nd day after Tl administration, which were completely normalized again at the 10th day. Other parameters such as Tl concentration, changes in water content and the activity of Na+/K(+)-ATPase as well as the diuretic effect of furosemide confirmed the Tl effect to be localized in the renal medulla. One single Tl administration is followed by a decrease in glomerular filtration rate (GFR) and urine volume and an increase of proteinuria. Electrolyte excretion was only slightly changed. All changes were reversible within the 10-day investigation period.
Animals↗
The ambiguous effect of ascorbic acid on chromate induced proteinuria in rats.
The influence of ascorbic acid (AA, 5 g/kg body weight) on chromate (Cr, 10 mg/kg) induced proteinuria, which is a sensitive parameter of its nephrotoxicity, was investigated in adult female Wistar rats. The concentrations of Cr and ascorbic acid (AA) were determined in renal tissue. Cr nephrotoxicity is related to its intracellular reduction from Cr(VI) to Cr(III). Proteinuria was completely prevented by enhancement of extracellular reduction of Cr(VI) to Cr(III) followed by rapid renal excretion when Cr and AA were given concomitantly. With an interval up to 1 h between Cr and AA, proteinuria was decreased probably by the radical scavenging function of AA. At an interval of 3 h AA enhanced Cr toxicity by increased intracellular Cr reduction. If the interval was increased to 5 h or if Cr was given 24 h after AA, no influence of AA could be detected. Our results confirm that AA is a very effective reductant of Cr which can influence Cr nephrotoxicity in very high concentrations. It depends on the interval between Cr and AA administration whether or not there is a beneficial effect of AA in Cr nephrotoxicity.
Animals↗
Ontogenic changes in the nephrotoxicity of chromate correlate with the glutathione oxidoreduction system.
The role of GSH concentration and GSSG reductase activity in age differences in chromate nephrotoxicity was investigated. Young and adult rats were injected with 2 and 1 mg sodium chromate/100 g body weight (BW), respectively, which led to equal Cr concentrations in renal tissue. Cr nephrotoxicity was lower in young than in adult rats. It was shown that from 30 minutes after the chromate injection GSSG reductase activity in renal tissue was increased in adult but decreased in young rats by the chromate. GSSG reductase activity was increased in young rats by pretreatment with phenobarbital. The consequence was an enhancement of chromate nephrotoxicity as shown by proteinuria. Renal GSH concentration is lower in young rats and limiting for chromate reduction in vitro in these animals. Therefore, GSH concentration was increased by pretreatment with N-acetylcysteine, which enhanced chromate nephrotoxicity significantly. These results reflect the important role of the GSH oxidoreduction system in chromate nephrotoxicity and its relationship to age differences.
Acetylcysteine↗
Role of glutathione for cisplatin nephrotoxicity in young and adult rats.
Investigations were done in 10- and 55-day-old Wistar rats. Glutathione (GSH) level in kidney was decreased by 8 mmol buthionine sulfoximine (BSO)/100 g BW. There was no effect on the renal function and nephrotoxicity of cisplatin (0.6 mg CP/100 g BW) in adult rats. In young rats BSO treatment was followed by nephrotoxic effects. Pt concentration remained unaffected by BSO in young and adult rats. GSH concentration in kidney was increased by 100 mg acetyl-cysteine (accys)/100 g BW. CP nephrotoxicity was lower in young as well as in adult ac-cys-treated rats. Pt levels in renal tissue were significantly decreased in rats from both age groups. From our results we conclude that the beneficial effect of high GSH concentration in renal tissue on CP nephrotoxicity is the result of decreased Pt concentration in kidney.
Acetylcysteine↗
Comparative nephrotoxicity studies of cisplatin and its iodinized derivative in rats.
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Animals↗
Chromate nephrotoxicity in developing rats. Significance of Cr(VI) reduction in rat kidney tissue.
Chromate reduction was studied in 9000 x g supernatant of renal tissue. It was shown that GSH plays an important role. Additionally, heat-sensitive factor(s) seem to be involved. Age differences in chromate nephrotoxicity parallel differences in chromate reduction in vitro. The lower reductive activity of young rats can be raised to adult values by GSH-addition. Fasting reduces GSH concentration, as well as chromate nephrotoxicity, in vivo.
Aging↗
Influence of metyrapone and phenobarbital on sodium dichromate nephrotoxicity in developing rats.
After the administration of equal doses of sodium dichromate, chromium concentrations in the kidney were lower in young than in adult rats. To test the age-dependent sensitivity to the nephrotoxicity of dichromate, young and adult rats were given doses to achieve identical chromium concentrations in the kidney. At equal renal concentrations, young rats had less functional and morphological damage than adult rats. As phenobarbital treatment in young rats enhanced the symptoms of nephrotoxicity and metyrapone treatment in adult rats decreased the symptoms of nephrotoxicity, age-dependent differences in chromate nephrotoxicity may be linked to an increase in the enzymatic reduction of Cr(VI) with age.
Aging↗
Triiodothyronine (T3) increases cisplatin nephrotoxicity in young and adult rats.
The influence of pretreatment with triiodothyronine (T3) on cisplatin (CP)-induced nephrotoxicity was investigated in 10- and 55-day-old rats. Triiodothyronine pretreatment enhanced CP proteinuria in young and adult rats, and increased blood urea nitrogen concentration in 55-day-old rats. As T3 decreased Pt concentrations in renal tissue, the enhanced nephrotoxicity of CP by T3 must have another mechanism. Enhanced CP nephrotoxicity is discussed in connection with an increase of glutathione concentration obtained in renal tissue as a consequence of T3 pretreatment.
Aging↗
The activity of chromate reduction in renal tissue corresponds to chromate nephrotoxicity--developmental aspects.
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Aging↗
Age dependent differences in the functional and morphological impairment of kidney following cisplatin administration.
In adult rats the clearance of inulin, urinary p-aminohippurate (PAH) excretion, TmPAH, as well as PAH accumulation in renal cortical slices were decreased 48-72 h following 0.6 mg cisplatin/100 g body mass (b.m.). Morphological investigations showed changes preferentially in proximal tubules. Reduced inulin clearance is discussed to be rather the consequence of inulin back leak in destroyed tubules than of a real decrease in glomerular function. The ultrastructure of glomeruli, distal tubules, and collecting ducts was not affected by cisplatin (CP) in 10- and 55-day-old rats. In 10-day-old rats, inulin clearance and urinary PAH excretion remained unaffected by CP, whereas TmPAH and PAH accumulation in vitro were significantly decreased following CP. Most significant ultrastructural changes occurring in mitochondria are discussed to cause decreased PAH accumulation following CP. The high portion of PAH filtered in young rats masked this impairment of active PAH secretion. Lower nephrotoxicity in young rats seems to be caused by low state of a differentiation of cell structure and transport function.
Age Factors↗
Metyrapone decreases the glutathione concentration in liver and kidney.
A single dose of 7.5 mg/100 g b.wt. metyrapone, intraperitoneally, decreased the concentration of reduced (GSH) and oxidized (GSSG) glutathione in the liver and kidney of female Wistar rats for approximately 4-5 h. The ratio between GSSG and GSH was not affected in the kidney but is decreased in the liver.
Animals↗
Age dependent differences in sodium dichromate nephrotoxicity in rats.
Investigations were performed on 10- and 55-day-old female Wistar rats. 1 or 2 mg sodium dichromate/100 g b. m. were administered subcutaneously. Urine was collected for 1 hour at different times after dichromate injection. Total urinary protein as well as some protein fractions (high and low molecular weight proteins as well as albumin) were determined. In adult rats dose dependence of nephrotoxicity was found concerning the extent and duration of renal damage. Separation of proteins gave an insight into the location of injury. At the beginning and in the recovery phase preferentially tubular damage was found. The peak of damage is characterized by additional glomerular disturbances. Young rats are much less susceptible to dichromate than adult rats are. Possible reasons are discussed.
Aging↗