Liver toxicity due to 1,2-dichloropropane in the rat

The effect of 1,2-dichloropropane on rat liver was studied after short (5 days) and long term (4 weeks) i.p. administration. Animals were injected daily with 10–500 mg/kg body wt 1,2-dichloropropane and biochemical and histological changes of liver were investigated. Treatment was monitored by measuring urinary mercapturic acid excretion. A significant increase of mercapturate excretion was observed at all dose levels, with no further increase during the treatment; at lower doses a return to baseline values occurred within 48 h after the end of treatment. Mercapturate excretion at the end of weeks 2, 3 and 4 of treatment was significantly lower than that observed at the end of week 1. The liver reduced glutathione content was different after single or repeated injections. A dose-dependent decrease of liver reduced glutathione was observed after a single injection and a dose-dependent increase after 4 weeks. The liver biochemical pattern after 4 weeks of treatment (characterized by a decrease of cytochrome P-450 and by an increase of reduced glutathione and glutathione S-transferase activity) suggests a hyperplastic evolution of the liver cells, probably a repair mechanism induced by early depletion of reduced glutathione. Light microscopy confimrs that the prevalent alterations are regenerative in type (atypical mithosis and hyperplastic nodules). Areas of focal necrosis are isolated, and trend to disappear after long term treatment.Some results were presented at the 1st Italian Symposium on: Mechanism of activation and toxicity of xenobiotics, Rome, 26–27 March 1987, and at the 50th National Congress of the Italian Society of Occupational Health and Industrial Hygiene, Rome, 21–24 October 1987     

Subchronic toxicity and carcinogenicity studies of 1,2-dichloropropane inhalation to mice

Abstract

The subchronic toxicity and carcinogenicity of 1,2-dichloropropane (DCP) in male and female B6D2F1 mice exposed to DCP by inhalation for 13 weeks or for 2 years was investigated. The DCP concentrations used were 50, 100, 200, 300 or 400?ppm (v/v) in the 13-week study, and 32, 80 or 200?ppm (v/v) in the 2-year study. Thirteen weeks inhalation exposure of mice to DCP caused death in the mice exposed to 300?ppm and above, and was found to induce hemolytic anemia and lesions of the liver, forestomach and heart. Two years exposure to DCP significantly increased the combined incidence of bronchiolo-alveolar adenomas and carcinomas in females and marginally increased the incidence of Harderian gland adenomas in males. As non-neoplastic lesion, atrophy and respiratory metaplasia in the olfactory epithelium, and respiratory metaplasia in the submucosal gland of the nasal cavity were increased. Thus, two years inhalation exposure to DCP is carcinogenic in female mice and there is a marginal evidence of carcinogenicity in males.     

Inhalation carcinogenicity and toxicity of 1,2-dichloropropane in rats

The toxicity and carcinogenicity of 1,2-dichloropropane (DCP) were examined by inhalation exposure of male and female F344 rats to DCP for either 13?wk or 2 years. In the 13-wk study, the DCP concentrations used were 125, 250, 500, 1000, or 2000?ppm (v/v), and in the 2-year study the DCP concentrations were 80, 200, or 500?ppm (v/v). Thirteen-week exposure to DCP induced hyperplasia in the respiratory epithelium and atrophy of the olfactory epithelium at 125?ppm and above. At the higher levels of exposure, hemolytic anemia and lesions of liver and adrenal gland were observed. Two-year exposure to DCP significantly increased incidences of papilloma in the nasal cavity of male and female rats exposed to 500?ppm DCP. In addition, three cases of esthesioneuroepithelioma were observed in the DCP-exposed male rats. Total nasal tumors increased in a concentration-dependent manner. Hyperplasia of the transitional epithelium and squamous cell hyperplasia, both of which were morphologically different from the hyperplasia of the respiratory epithelium observed in the 13-wk exposure study, occurred in a concentration-dependent manner; these lesions are considered to be preneoplastic lesions. Atrophy of the olfactory epithelium, inflammation of the respiratory epithelium, and squamous cell metaplasia were also seen in the 2-year study. These results demonstrate that DCP is a nasal carcinogen in rats. Lifetime cancer risks for humans exposed to DCP in the ambient air and work environment were quantitatively estimated, using both nonthreshold and threshold approaches, with the data obtained from the 2-year study.     

Effect of sex hormone status on chloroform nephrotoxicity and renal mixed function oxidases in mice

In mice, only makes are susceptible to chloroform (CHCl₃) nephrotoxicity and the susceptibility appears to be related to renal mixed function oxidase activity. There were sex-related differences of renal cytochrome P-450 and b₅ concentrations and of ethoxycoumarin O-deethylase activity in mouse kidneys; in all cases activity was higher in males. Castration of male mice eliminated susceptibility to ChCl₃ nephrotoxicity and reduced renal mixed function oxidases to concentrations observed in female mice. Treatment of male and female mice with testosterone increased the susceptibility to ChCl₃ nephrotoxicity and increased renal mixed function oxidases to similar activities in both sexes. Previous data have suggested that CHCl₃ is metabolized in situ by the kidney, possibly by a mechanism similar to that occurring in the liver. The data from this investigation are consistent with the concept that CHCl₃ is metabolized by a cytochrome P-450-dependent mechanism in the kidney.     

Degree of ethoxyquin-induced nephrotoxicity in rat is dependent on age and sex

The toxicity of ethoxyquin (EQ) to rat kidney was examined in males which were either weanling or adult at the beginning of the experiment, and also in adult females. Female rats were much less susceptible to the toxic effects of EQ than males of the same age. In males damage to the cortex, mainly as an acceleration of the normal ageing process, was similar in both age groups, but rats exposed to EQ as weanlings also suffered from extensive papillary necrosis. Male rats were more prone than females to proteinuria, which was greatly exacerbated by EQ in both age groups. Thus there is very little evidence of nephrotoxicity in adult female rats on exposure to EQ at 0.5% in the diet for 26 weeks. In males, the initial age of the animal, as well as the length of treatment, influences the extent of damage.     

1,2-Diazole prevents cisplatin-induced nephrotoxicity in experimental rats

BackgroundCisplatin (a platinum-compound) is a anti-neoplastic drug used in the treatment of various cancers but eventually results in severe adverse effects namely nephrotoxicity or renal disorder through generation of reactive oxygen species (ROS). This biochemical measurements and histopathology analysis investigated a possible protective effect of 1,2-diazole with regards to cisplatin-induced nephrotoxicity in experimental animals.MethodsAnimals were divided into four groups of six mice each. Group A: normal control, vehicle (1 % (w/v) gum acacia in phosphate buffer saline (PBS)). Group B: cisplatin group, vehicle + cisplatin (7.5 mg/kg). Group C: 1,2-diazole (10 mg/kg) + cisplatin and Group D: silymarin (50 mg/kg) + cisplatin. Each vehicle/drug treatment was given daily via intraperitoneal (ip) injection for 10 consecutive days starting from day 1. On group B, C and D cisplatin was given in single dose only on day 5 one hour post drug administration. Animals were allowed till 10^th day and on day 11 all four groups animals were anesthetized. Blood samples were collected and serum was isolated for biochemical measurements. The rats were then euthanized by cervical dislocation and their kidney was recovered and then prepared for biochemical measurements and histopathology analyses.ResultsPretreatment with 1,2-diazole prevented nephrotoxicity induced by cisplatin through a protective mechanism that involved reduction of increased oxidative stress by significantly increasing the enzymatic and non enzymatic antioxidant enzymes such as glutathione peroxidase (GPx), glutathione (GSH) and diminishing the lipid peroxidation (LPO). The pretreatment with 1,2-diazole does not affect superoxide dismutase (SOD), catalase (CAT), serum urea and creatinine level during nephrotoxicity when compared to cisplatin-induced group. Moreover, the 1,2-diazole animals shown significant decrease in urine volume and kidney weight when compared with cisplatin-induced group. Histopathological findings reveals the protective efficacy of 1,2-diazole that restores histopathological changes against nephrotoxicity.ConclusionThese analysis will provide a critical evidence that 1,2-diazole could provide a new protective strategy against cisplatin-induced nephrotoxicity.     

Species differences in the nephrotoxic response to S-(1,2-dichlorovinyl)glutathione.

The present study was carried out to investigate the species differences in the nephrotoxic response to S-(1,2-dichlorovinyl)glutathione (DCVG) using rats, hamsters and guinea-pigs. DCVG was given intraperitoneally in physiological saline to groups of 5 animals at doses 0, 165 and 330 μmol/kg. Urine was collected for 24 h and the animals were then sacrificed. Significantly increased levels of urinary glucose, , γ-glutamyl transpeptidase, proteins and blood urea nitrogen were observed in rats at both dose levels of DCVG. An increase, but not of similar magnitude, of these biochemical parameters was noted in hamsters only at the higher dose of DCVG. Guinea-pigs showed significant increases in these biochemical parameters at the lower dose, but not at the higher dose. Light-microscopic studies showed increasing proximal tubular necrosis (PTN) in rats with increasing dose of DCVG, but PTN involving straight tubules only was observed at the higher dose in hamsters. PTN was again observed in guinea-pigs at the lower dose, but not at the higher dose of DCVG.     

In vitro study of putative genomic biomarkers of nephrotoxicity through differential gene expression using gentamicin

Drug-induced nephrotoxicity is one of the most frequently observed effects in long-term pharmacotherapy. The effects of nephrotoxicity are commonly discovered later due to a lack of sensitivity in in vivo methods. Therefore, researchers have tried to develop in vitro alternative methods for early identification of toxicity. In this study, LLC-PK1 cells were exposed to gentamicin through MTT and trypan blue assay. Concentrations of 4 (low), 8 (medium) and 12 (high) mM, were used to evaluate differential gene expression. A panel of genes was selected based on gene expression changes. The search for sequences of mRNA encoding proteins previously associated with kidney damage was conducted in the databases of the National Center for Biotechnology Information (USA). RNA was extracted from the cells, and RT-qPCR was performed to evaluate differential expression profiles of the selected genes. Among the 11 analyzed genes, four proved to be differentially up-regulated in cells exposed to gentamicin: HAVcr1, caspase 3, ICAM-1 and EXOC6. According to this study’s results, we suggest that these genes play an important role in the mechanism of in vitro nephrotoxicity caused by gentamicin and can be used as early in vitro biomarkers to identify nephrotoxicity when developing safer drugs.     

Inhalation carcinogenicity and toxicity of 1,2-dichloropropane in rats

The toxicity and carcinogenicity of 1,2-dichloropropane (DCP) were examined by inhalation exposure of male and female F344 rats to DCP for either 13 wk or 2 years. In the 13-wk study, the DCP concentrations used were 125, 250, 500, 1000, or 2000 ppm (v/v), and in the 2-year study the DCP concentrations were 80, 200, or 500 ppm (v/v). Thirteen-week exposure to DCP induced hyperplasia in the respiratory epithelium and atrophy of the olfactory epithelium at 125 ppm and above. At the higher levels of exposure, hemolytic anemia and lesions of liver and adrenal gland were observed. Two-year exposure to DCP significantly increased incidences of papilloma in the nasal cavity of male and female rats exposed to 500 ppm DCP. In addition, three cases of esthesioneuroepithelioma were observed in the DCP-exposed male rats. Total nasal tumors increased in a concentration-dependent manner. Hyperplasia of the transitional epithelium and squamous cell hyperplasia, both of which were morphologically different from the hyperplasia of the respiratory epithelium observed in the 13-wk exposure study, occurred in a concentration-dependent manner; these lesions are considered to be preneoplastic lesions. Atrophy of the olfactory epithelium, inflammation of the respiratory epithelium, and squamous cell metaplasia were also seen in the 2-year study. These results demonstrate that DCP is a nasal carcinogen in rats. Lifetime cancer risks for humans exposed to DCP in the ambient air and work environment were quantitatively estimated, using both nonthreshold and threshold approaches, with the data obtained from the 2-year study.     

关木通肾脏毒性研究及对策

针对某些含马兜铃酸中草药引起肾脏损害的临床报道,开展对关木通肾脏毒性的文献收集及临床和实验的系统研究,并提出了相应的对策.为正确认识木通品种及其效用的异同,指导临床安全高效用药提供了依据.     

Ontogenic aspects of cisplatin-induced nephrotoxicity in rats

A multi-age rat model was evaluated to identify a potential age-related difference in kidney injury following administration of cisplatin (CP). Different age groups of Wistar rats (aged 3, 7, 11 and 24 weeks) were given CP intraperitoneally (6 mg/kg) and sacrificed 6 days thereafter. CP-induced nephrotoxicity caused significant decreases in body weight, creatinine clearance, urine osmolality, plasma total anti-oxidant status, cortical glutathione (GSH) concentration and superoxide dismutase activity.It increased kidney weight and plasma concentrations of creatinine and urea. It increased urinary N-acetyl-β-d-glucosaminidase activity and protein concentration. Most of the above actions were more marked as the animals advanced in age, except for the changes in GSH, which were similar in all age groups.     

Cyclosporine-loaded polycaprolactone nanoparticles: immunosuppression and nephrotoxicity in rats

Aim: The nephrotoxicity and immunosuppressive ability of cyclosporine (CyA) incorporated into polycaprolactone nanoparticles (CyA-NP) was assessed in vitro and in vivo and compared to the effects caused by free drug (Sandimmun^®). Methods: The in vivo study included four groups (12 Wistar rats each) receiving oral CyA (10 mg/kg/day for 3 days) as an emulsion of Sandimmun in whole milk or CyA-NP and equivalent doses of empty NP or cremophor^® in milk as controls. CyA concentrations in blood, urine, liver, spleen and kidney at 24 h post-dosing were measured by fluorescence polarization immunoassay (FPIA). The nephrotoxicity induced by each drug treatment was determined by measuring creatinine plasma levels, malonyl dialdehyde production, and H₂O₂ and reduced glutathione contents in glomeruli. On the other hand, the immunosuppressive effect was estimated in vivo by incubating lymphocyte suspensions obtained from CyA-, CyA-NP- and control-treated rats, as well as in vitro on lymphocyte suspensions from non-treated healthy animals. Results: Significantly higher blood, urine and tissue levels were achieved with CyA-NP compared to free CyA. However, no changes in creatinine plasma levels were detected due to either CyA or CyA-NP treatment. Only the production of H₂O₂ in the glomeruli exhibited a significant increase as compared to control groups, but no differences could be ascribed to the different drug treatments. In vivo, the immunosuppressive activity was also comparable for both drug treatments. In contrast, CyA-NP showed a better drug uptake in vitro at concentrations above 25 μM. No immunosuppression was detected in control groups. Conclusion: NP improve the oral bioavailability of CyA and its uptake by lymphocytes in vitro above 25 μM. On the contrary, specific immunosuppression and adverse effects were not simultaneously increased. Further studies are needed to clarify the results.     

Prevention of lithium nephrotoxicity in a novel one-hour model in rats

It is well established that lithium can cause morphologically visible damage to the kidneys of humans and animals. Although the clinical significance of its nephrotoxicity is debatable, it would be desirable to find a method to prevent lithium’s effect on the kidneys. Toward this end, we have developed a novel method for producing nephrotoxicity that will be useful for research on prevention. A single, large, toxic dose of lithium chloride (LiCl) caused necrosis of the distal convoluted tubules, which was visible by light microscopy in 30 min, had fully developed in 1 h, and had disappeared by the next day. The lesions were seen after IP or IV injections of fasted rats of three different strains. Equivalent doses of NaCl, KCl, MgCl₂ and combinations thereof had no such effect, nor did they inhibit nephrotoxicity when incorporated into the LiCl solution. However, relatively small doses of LiCl injected by any route 3 or 24 h beforehand prevented the nephrotoxicity. The mechanism of prevention is not known, but it does not involve reduction of lithium levels in the kidneys. Received: 30 July 1997/Final version: 18 November 1997     

Resveratrol attenuates cisplatin-induced nephrotoxicity in rats

Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.     

多黏菌素E肾毒性机制研究进展

近年来，院内多重耐药革兰阴性菌感染形势日趋严峻，老药多黏菌素E(colistin)重新成为临床选择。对于耐药菌感染增加colistin剂量能够获得更好疗效，但具有增加肾脏的毒性风险。本文就colistin的肾毒性作用机制研究进行综述，包括其对肾的直接毒性作用、激活经线粒体、死亡受体和内质网的细胞凋亡通路，以及抑制自噬对肾损伤的保护作用等；同时，本文还归纳了对于colistin诱导的肾损伤具有潜在的保护作用的药物，旨在为临床合理应用colistin降低其肾毒性提供相关数据支持。     

Effect of Sairei-to on gentamicin nephrotoxicity in rats

The effect of Sairei-to, an oriental traditional medicine, against gentamicin nephrotoxicity was examined in gentamicin nephrotoxicity rat models. Gentamicin nephrotoxicity was induced by s. c. injection of gentamicin (100 mg/kg/day, for 3 days) in male Sprague-Dawley rats. Renal functions of two rat groups were compared, one eating rat chow containing 2.5% Sairei-to, the other eating normal rat chow. Sairei-to administration reduced the increase of urinary N-acetyl--D-glucosaminidase (NAG) and protein excretion, and decreased creatinine clearance induced by gentamicin. Gentamicin increased renal cortical malondialdehyde (MDA) concentration in normal diet group but not in the Sairei-to diet group. The renal cortical gentamicin concentration was not different between the two groups. In conclusion, Sairei-to shows reno-protective action against gentamicin nephrotoxicity, possibly through its anti-oxidant action.     

Species differences in the nephrotoxic response to S-(1,2-dichlorovinyl)glutathione

The present study was carried out to investigate the species differences in the nephrotoxic response to S-(1,2-dichlorovinyl)glutathione (DCVG) using rats, hamsters and guinea-pigs. DCVG was given intraperitoneally in physiological saline to groups of 5 animals at doses 0, 165 and 330 . Urine was collected for 24 h and the animals were then sacrificed. Significantly increased levels of urinary glucose, N-acetyl-β-d-glucosaminidase, γ-glutamyl transpeptidase, proteins and blood urea nitrogen were observed in rats at both dose levels of DCVG. An increase, but not of similar magnitude, of these biochemical parameters was noted in hamsters only at the higher dose of DCVG. Guinea-pigs showed significant increases in these biochemical parameters at the lower dose, but not at the higher dose. Light-microscopic studies showed increasing proximal tubular necrosis (PTN) in rats with increasing dose of DCVG, but PTN involving straight tubules only was observed at the higher dose in hamsters. PTN was again observed in guinea-pigs at the lower dose, but not at the higher dose of DCVG.     

Sex- and age-related variation in metal content of penguin feathers

The presence of xenobiotics, such as metals, in ecosystems is concerning due to their durability and they pose a threat to the health and life of organisms. Moreover, mercury can biomagnify in many marine food chains and, therefore, organisms at higher trophic levels can be adversely impacted. Although feathers have been used extensively as a bio-monitoring tool, only a few studies have addressed the effect of both age and sex on metal accumulation. In this study, the concentrations of trace elements were determined in the feathers of all members of a captive colony of African Penguins (Spheniscus demersus) housed in a zoological facility in Italy. Tests were performed by inductively coupled plasma-mass spectrometry to detect aluminum, arsenic, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead, selenium, tin, vanadium, and zinc. Mercury was detected by a direct mercury analyzer. Sexing was performed by a molecular approach based on analyzing the chromo-helicase-DNA-binding1 gene, located on the sex chromosomes. Sex- and age-related differences were studied in order to investigate the different patterns of metal bioaccumulation between male and female individuals and between adults and juveniles. Juvenile females had significantly higher arsenic levels than males, while selenium levels increased significantly with age in both sexes. Penguins kept in controlled environments—given that diet and habitat are under strict control—represent a unique opportunity to determine if and how metal bioaccumulation is related to sex and age.     

Pharmacokinetics and nephrotoxicity of aristolochic acid in rabbits

Aristolochic acids (AAs) which exist in plants of the genus Aristolochia are the toxins responsible for aristolochic acid nephropathy (AAN). To investigate the pharmacokinetics and nephrotoxicity of AAs, rabbits were used in this study. The plasma concentrations of the main components of AAs, aristolochic acid I (AA I) and aristolochic acid II (AA II), were determined by a validated high-performance liquid chromatographic method. After intravenous administration of different doses (0.25, 0.5, 1.0, and 2.0 mg/kg) of aristolochic acid sodium (AANa) to 4 respective groups of rabbits (n=6 for each dose), linear relationships between the doses of AA I and AA II and the area under the plasma concentration curve (AUC) were found to exist (p<0.001). AANa was also given in escalating doses (0.5, 1.0, and 2.0 mg/kg) to the same rabbits at 7-day intervals. The clearance rates of both AA I and AA II significantly decreased with the escalating dose (p<0.001). A nonlinear relationship between the dose and AUC was obtained. Kidney specimens of rabbits were obtained to observe morphological changes on days 1 and 7 after AANa administration. The renal lesions caused by AAs consisted of progressive and dose-dependent tubular damage. However, no remarkable changes in the morphology of glomeruli were observed.