1,720,962 research outputs found
Different effects of (cis+trans) 1,3-dichloropropene in renal cortical slices derived from male and female rats.
Full text linkNephrotoxic effects of 1,3-dichloropropene (cis and trans isomers mixture) was investigated in vitro by means of renal cortical slice model in male and female rats, including treatment with metabolism modifiers as an inducer of cytochrome P-450 1A class (beta-naphthoflavone), a reduced glutathione depleting (DL-buthionine-[S,R]-sulfoximine), an inhibitor of gamma-glutamyl-transferase (AT-125) and inhibitor of cysteine conjugate beta-lyase (aminooxiacetic acid). Dose-dependent decrease of p-aminohippurate uptake was observed in male renal cortical slices. Only the high doses (3.0 and 4.0 x 10(-4) M) caused a significant loss of organic anion uptake in females. beta-Naphthoflavone and alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) partially, but significantly, reduced organic anion loss in males. In females, DL-buthionine-[S,R]-sulfoximine significantly increased in females but in males loss of organic anion accumulation caused by 1,3-dichloropropene. Aminooxyacetic acid did not ameliorate 1,3 D effects in vivo and in vitro in male rats. It appeared very toxic for female rats (all rats died) after in vivo injection. Sensitivity to nephrotoxicity induced by 1,3-dichloropropene in vitro was about double in male than female rats. Reduced glutathione conjugation appeared involved in nephrotoxicity induced in males but in females, probably by means of a chloropropyl-cysteinylglycine-conjugate formation; slight toxicity in females is likely related to oxidative metabolism
Nephrotoxicity of 1,3-dichloropropene in vitro and effects of metabolism modifiers
No full text1,3-Dichloropropene (1,3-D) is largely used in agriculture as a soil fumigant. The few reports on toxicological effects show that liver and kidney are the main targets. The current research assesses the effects caused by 1,3-D dissolved in ethanol (0.2-1.6 mmoles/incubation) in male and female rats, related to metabolism modifiers, by means of renal cortical slice technique. The accumulation of the organic anion p-aminohippurate (PAH) was used as an index of toxicity. Groups of rats were also pretreated with DL-buthionine [S,R]-sulfoximine (BSO), inhibitor of GSH content, or ß-naphthoflavone (NF), activator of the CYP-450 A family. After pretreatment with BSO (500 mg/kg b.w. 4 h before sacrifice), or NF (80 mg/kg b.w., once a day fro three days before sacrifice), renal cortical slices were prepared and treated in vitro with 1.2 mmoles/incubation (toxic dose for female also) of 1,3-D. A dose-dependent decrease in PAH accumulation was observed in male and female rats, but the female rats were susceptible to the higher dose only, and the decrease was significantly lower than males. NF ameliorates the loss of PAH uptake caused by 1,3-D in the male rat, whereas BSO had an additive effect on the loss of PAH uptake caused by 1,3-D in the female rat. These results show that PAH accumulation is more susceptible in male than in female rats to the effects of 1,3-D and induction of A subfamilies of CYP-450 significantly prevents the loss of PAH accumulation induced by 1,3-D in male rats, but not in female rats. On the contrary, GSH depletion increases 1,3-D toxicity in female, but not in male rats. In conclusion, sex differences of 1,3-D toxicity may be explained by difference in metabolic pathways where GSH appears to play a pivotal role in the detoxification of 1,3-D in female rats, but not in males
Mechanism of sex-related differences in nephrotoxicity of 1,2-dichloropropane in rats.
Full text linkThe contribution of testosterone to the nephrotoxic effects of 1,2-dichloropropane (DCP) was assessed by a series of castration and sex hormone replacement experiments on Wistar rats. The nephrotoxic action of DCP was evaluated by measuring the accumulation of organic anion and release of aspartate aminotransferase into the incubation medium using a renal cortical slice model. Our data show that sex, castration, and testosterone pretreatment are factors that influence the effect of DCP on renal cortical slices of rats. Males appear to be more sensitive to nephrotoxic effects of DCP than females, male castration prevents the nephrotoxic effects of DCT: and pretreatment of females and castrated males with testosterone increases the susceptibility to DCP. In this study an attempt was made to evaluate the role of sex differences in the expression of enzymes participating in Phase I and Phase II detoxication reactions in order to explain the differences in sensitivity of the two genders to the nephrotoxic action of DCP. Our results implicate gender-specific expression of cytochrome P-450 in the kidney as a predominant factor that determines the different susceptibilities of male and female rats to the nephrotoxic effect of DCP. We propose that the oxidation of DCP by CYP IIEI is the first saturable and limiting step in the metabolic activation of DCP to nephrotoxic metabolites. It appears that, despite the fact that the nephrotoxic effect of DCP is determined mainly by its cysteine-conjugated metabolites, glutathione (GSH) content and glutathione S-transferase (GST) activity in kidney are nor directly I related to increased androgen-related susceptibility to DCP. Since there were no significant differences in studied parameters of the liver in the genders, it is also possible to assume that DCP oxidative metabolism and glutathione conjugation in liver do not play an important role in the gender-specific susceptibility of rats to the nephrotoxic effect of DCP
Sex- and age-related nephrotoxicity due to 1,2-dichloropropane in vitro.
Full text linkSex- and age-related nephrotoxicity due to 1,2-dichloropropane was studied in vitro by means of renal cortical slices obtained from Wistar rats. Reduced glutathione content, organic anion accumulation (p-aminohippurate), and release of malondialdehyde (to measure the extent of lipid peroxidation), aspartate aminotransferase, gamma-glutamyltransferase and lactate dehydrogenase into the incubation medium were determined. Sex differences in naive rats parameters were slight, but male were more susceptible to toxic effects of 1,2-dichloropropane than female rats; glutathione depletion, lipid peroxidation, and loss of organic anion accumulation were higher in male than in female slices. During senescence, naive male rats showed a progressive decrease of glutathione content (statistically significant from 7-9 months of age), increase of spontaneous lipid peroxidation from the same age, and increase of signs of cytotoxicity (release of aspartate aminotransferase and lactate dehydrogenase into the incubation medium) from 3-4 months of age. A loss of organic anion accumulation started from 7-9 months of age. Slices from rats of 3-4 months old showed the apparently highest susceptibility to 1,2-dichloropropane but depletion of glutathione content and loss of organic anion accumulation were at the same level in the oldest rats. The age decrease of control values caused the differences in the percentage ratio and then, apparently, a lower DCP effect. On the contrary, the increase of aspartate aminotransferase released in the incubation medium by DCP-treated slices corresponded to the age-related increase in cytotoxicity
Role of in vivo cysteine conjugate ß-lyase inhibition on nephrotoxicity due to 1,2-dichloropropane in vivo and in vitro
No full text“In vivo” and “in vitro” pretreatment with aminooxyacetic acid (AOAA), a specific inhibitor of renal cysteine conjugate ß-lyase (ß-lyase) activity, protects against S-conjugates-induced nephrotoxicity. In order to study “in vivo” and “in vitro” nephrotoxic effects of 1,2-dichloropropane (DCP), male Wistar rats were given AOAA 0.5 mmole/kg i.p. 1 hour before “in vivo” treatment with DCP (4.4 mmoles/kg i.p.), or the sacrifice for “in vitro” studies carried out by means of the renal cortical slice model. DCP concentration of 25x10-3 M was used for “in vitro” experiments. “In vivo” DCP-treated rats were sacrificed ten hours after dosing, because preliminary experiments showed the maximum reduced glutathione depletion after this time. DCP “in vivo” treatment caused a significant (p<0.005) loss of organic anion accumulation (measured by means of p-aminohippurate), increase of blood urea nitrogen (p<0.05) and urinary protein excretion (p<0.001); “in vitro” treatment caused a significant lipid peroxidation (p<0.001), measured by means of malondialdehyde release in the incubation medium, and loss of organic anion accumulation (p<0.001). AOAA pretreatment prevents “in vivo” and “in vitro” DCP nephrotoxicity almost totally. Data show that DCP-induced nephrotoxicity is via the mercapturic acid pathway with activation of the cysteine conjugate to a nephrotoxic thiol, and confirm our previous research “in vitro” that also haloalkane nephrotoxicity may be mediated via ß-lyase activation
Urinary excretion of glutamine transaminase K as an early index of mercuric chloride-induced nephrotoxicity.
Full text linkThe possibility that urinary glutamine transaminase K activity might be a marker of a proximal tubule segment-specific response to mercuric chloride was investigated in male rats after a single i.p. injection in time-course and dose-response experiments. Urinary total proteins and angiotensin converting enzyme activity were determined simultaneously. Urinary indices showed an early increase (within 5 h of treatment) of total proteins and angiotensin converting enzyme, whereas glutamine transaminase K increased 10 h after treatment. The peak of all these indices was observed 24 h after mercuric chloride injection. The lowest dose that induced a significant increase in proteins and enzymes was 0.25 mg kg(-1); in addition, a dose-response effect was observed. Glutamine transaminase K appeared to be an early and sensitive index of response of mercuric chloride effects, similar to total proteins and angiotensin converting enzyme. It is suggested that this enzyme is mainly localized in the 'pars recta' of the proximal tubule. Therefore glutamine transaminase K might be a segment-specific marker for the detection of damage localized in this portion of the proximal tubule
Glutamine synthetase (GS) activity in urine as index of segment-specific injury
No full textGS, a mitochondrial enzyme present in a variety of tissues including kidney, is responsible for the production of glutamine from glutamate. In the kidney, it is localized only in the early and late portion of the pars recta of the proximal tubule. This exclusive localization may be used to study, without invasive and difficult to achieve methods, the effects of nephrotoxicants on the straight portion of the proximal tubule. Male, two months old, Wistar rats were treated with 1.0 mg/kg b.w. i.p. of mercuric chloride (Hg2+) or 100 mg/kg b.w. i.p. of hexachloro-1:3-butadiene (HCBD), both chemical specific toxicants for the straight portion, or 25 mg/kg b.w. s.c. of potassium dichromate (Cr6+), specific toxicant for the convoluted portion. Urines were collected 14 hours before and every 10 or 14 hours until 96 hours after treatment. At the same time of urine collection, histological examination of the kidney of an ancillary group treated with the same doses was performed. The results show a peak of GS excretion 24 hours after treatment with Hg2+ or HCBD, related to focal (Hg2+) or diffuse (HCBD) necrosis of the pars recta. After the peak of excretion, enzyme activity in urine decreases progressively until the end of the observation period, but it doesn’t normalize, though regeneration of the cell of the pars recta was almost complete after 96 hours for both chemicals. On the contrary, treatment with Cr6+ doesn’t affect GS excretion in urine until 72 hours after treatment, when a slight excretion of the enzyme is related to the histological findings of a focal vacuolization of the pars recta. High excretion of the enzyme appears related to the necrosis of the straight segment, because damage without necrosis, as induced by Cr6+, causes only a slight excretion. This fact may be explained by the mitochondrial localization, organelles highly sensitive to the necrosis. In conclusion, specific injury of the proximal straight tubule may be well defined by means of urinary GS. In our opinion, segment-specific injury by nephrotoxicants may be measured by means of tubular enzymes. In addition, segment-specific origin may be defined by means of segment-specific nephrotoxicants
Biological monitoring of cadmium exposure: reliability of spot urine samples
Full text linkConcentration-dilution of spot urine samples is a shortcoming of the biological monitoring of industrial xenobiotics. To ascertain whether the adjustment of urinary cadmium measured in spot samples is appropriate, urine samples were taken three times, once a week for 3 successive weeks, from 25 welders employed in the manufacture of jewelry (total 75 samples). Cadmium, creatinine, specific gravity, total urinary solutes, urinary volume and urinary flow rate were measured in 12-h collections and in spot samples taken immediately afterwards. Creatinine and total urinary solutes showed high inverse correlation with urinary flow rate (r = -0.858 and r = -0.768 respectively). Urinary cadmium displayed a similar trend but the correlation was not significant (r = -0.145). Creatinine adjustment of urinary cadmium values in spot samples increased the correlation with the same index in timed samples adjusted for urinary volume (r = -0.808) or urinary flow rate (r = 0.821) compared with non-adjustment (r = 0.732 and r = 0.738, respectively). Creatinine adjustment of spot sample values is also suitable for a wide range of urinary concentrations; discarding excessively diluted or concentrated urines, correlation of urine samples improved for non-adjusted or specific gravity-adjusted values, whereas no changes were observed for creatinine-adjusted values
- …
