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Archives of Toxicology (v.79, #8)

Differential effects of diabetes on CYP2E1 and CYP2B4 proteins and associated drug metabolizing enzyme activities in rabbit liver by Emel Arınç; Şevki Arslan; Orhan Adalı (pp. 427-433).

The effects of diabetes on cytochrome P450 (CYP)-dependent drug metabolizing enzymes are yet to be clarified. The most widely used animals in these studies have been rats, and information on the effects of diabetes on rabbit liver drug metabolizing enzymes have been unavailable until now. In this study, for the first time, a significant induction of liver CYP2E1 is demonstrated via immunoblot analysis in alloxan-induced rabbits. The CYP2E1 content of diabetic microsomes was highly correlated with the activities of liver aniline 4-hydroxylase (r=0.82, p<0.05), and p-nitrophenol hydroxylase (r=0.86, p<0.01), and diabetes increased the activities of the enzymes associated with CYP2E1. The activities of aniline 4-hydroxylase and p-nitrophenol hydroxylase were significantly increased by 1.7 and 1.8-fold, respectively compared to those of control rabbits. In marked contrast, diabetes had no effect on the protein levels of CYP2B4 as determined by immunoblotting and on benzphetamine N-demethylase activity, which is known to be specifically metabolized by CYP2B4 in rabbit liver. The present study demonstrates that diabetes increases the activities of CYP2E1 and associated enzymes but does not change the activity levels of CYP2B4 and associated enzymes in diabetic rabbits. These findings are in contrast to those of mice, hamsters and rats, and that suggest the presence of species-dependent responses of CYP-dependent drug metabolizing enzymes to diabetes.

Keywords: Diabetes; Rabbit liver; Induction; CYP2E1; CYP2B4; Aniline 4-hydroxylase

Hepatotoxic and nephrotoxic effects of Cadmium in the frog Rana ridibunda by Nikolaos S. Loumbourdis (pp. 434-440).

Histological and histochemical alterations in the liver and kidneys of the frog Rana ridibunda, which was exposed to 200 ppm aqueous solutions of cadmium for 4, 10 and 30 days, respectively were investigated. In both the liver and kidneys, essential changes appeared after 10 days’ exposure, the maximum changes being apparent after 30 days of exposure. In the liver, what was very characteristic was an increase in the area occupied by Kupffer cells, with the area in the animals exposed to cadmium for 30 days being the largest observed. What was also apparent was karyomegaly, polyploidy and infiltration. In addition with regard the kidneys, Hyaline Globules (HG) and apoptotic bodies occurred at a higher rate. At 30 days’ exposure, most of the above changes were enhanced. In comparison with 10 days’ exposure, fibrosis around the blood vessels and between hepatocytes, as well as Proliferating Cell Nuclear Antigen (PCNA) reactivity and apoptotic bodies increased lightly in the liver. In the kidneys, the most pronounced changes were the increase in numbers of apoptotic bodies, PCNA reactivity and hyaline globules. It was concluded that the variability in positive reactions for various proteins in the hyaline globules may be an indication that these (and possibly other) proteins are synthesized by tumor cells, but, most probably, that they may represent liver damage, progressive nephropathy, or progressive glomerulonephropathy.

Keywords: Cadmium; Histopathology; Liver; Kidney; Frog

Indomethacin induces free radical-mediated changes in renal brush border membranes by J. Basivireddy; M. Jacob; K. A. Balasubramanian (pp. 441-450).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in clinical medicine. One disadvantage of their use, however, is the occurrence of adverse effects in the kidneys. The side effects produced in this organ have been classically attributed to the inhibitory effect of these drugs on the activity of cyclooxygenase, a key enzyme in prostaglandin synthesis. Our earlier work with indomethacin, a commonly used NSAID, has shown that oxidative stress and mitochondrial dysfunction occur in the kidney in response to the drug. In view of this, this study looked into the effect of indomethacin on brush border membranes (BBM) from the kidney, as these biomembranes are prime targets of oxygen free radicals. Rats, fasted overnight, were dosed with indomethacin (20 mg/kg) by gavage and sacrificed 24 h later. BBM were isolated from the kidneys by polyethylene glycol precipitation. It was found that there was an increase in levels of products of peroxidation and a fall in the level of alpha-tocopherol in the BBM from indomethacin-dosed rats. These BBM also exhibited impaired glucose transport. The lipid composition of the membranes was also found to be altered. Alterations in lipids were associated with up-regulation of phospholipase A₂. Pretreatment with L-arginine, a nitric oxide donor, protected against these effects of indomethacin. Thus, this study suggests that indomethacin induces impairment in structure and function of BBM in the kidney, with these effects possibly mediated by free radicals and activation of phospholipases. We postulate that such alterations may be important in the pathogenesis of NSAID-induced nephropathy.

Keywords: Brush border membrane; Kidney; Indomethacin; Nitric oxide; Nonsteroidal anti-inflammatory drugs; Oxidative stress

Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats by Takeki Uehara; Hiroshi Watanabe; Fumio Itoh; Satoshi Inoue; Hikaru Koshida; Masuhisa Nakamura; Jyoji Yamate; Toshiyuki Maruyama (pp. 451-460).

The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, γ-GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.

Keywords: Nedaplatin; Cisplatin; Nephrotoxicity; Papillary lesions; Rats

Contribution of flavonoid antioxidants to the preventive effect of mesna in cyclophosphamide-induced cystitis in rats by Ayhan Ozcan; Ahmet Korkmaz; Sukru Oter; Omer Coskun (pp. 461-465).

Cyclophosphamide (CP) is widely used, alone or in combination with other chemotherapeutic agents, for treatment of neoplastic diseases. Its urotoxicity may cause dose-limiting side-effects, for example hemorrhagic cystitis. The agent most often used to prevent this side-effect is mesna (2-mercaptoethane sulfonate). Overproduction of reactive oxygen species during inflammation is one reason for possible urothelial injury. The aim of this study was to evaluate whether combinations of quercetin and epigallocatechin 3-gallate (EGCG), flavonoid antioxidants and mesna could prevent cystitis induced by cyclophosphamide, better than mesna alone. A total of 38 male Sprague–Dawley rats were divided into five groups. Four groups received single dose of CP (100 mg kg⁻¹) intraperitoneally at the same time. Group 2 received CP only, group 3 received mesna (3×21.5 mg kg⁻¹), group 4 received a single dose of mesna+EGCG (2×20 mg kg⁻¹), and group 5 received a single dose of mesna+quercetin (2×20 mg kg⁻¹), before and after CP injection. Group 1 (not treated) served as control. CP injection alone resulted in severe cystitis. Mesna resulted in some, but not full, protection against CP toxicity. Quercetin and catechine, together with mesna, resulted in full protection against CP toxicity, on the basis of histopathology of the urinary bladder. It was concluded that oxidants might be important in the pathogenesis of CP-induced cystitis, and that flavonoid antioxidants, used in addition to mesna, may help to ameliorate bladder damage.

Keywords: Cyclophosphamide; Cystitis; Flavonoids; Mesna

Platelet-activating factor (PAF) involvement in acetaminophen-induced liver toxicity and regeneration by A. D. Grypioti; S. E. Theocharis; G. K. Papadimas; C. A. Demopoulos; Z. Papadopoulou-Daifoti; A. C. Basayiannis; M. G. Mykoniatis (pp. 466-474).

Acetaminophen-induced toxicity has been attributed to cytochrome P-450-generated metabolites, which covalently modify target proteins. However, the mechanism of liver injury pathogenesis needs to be further elucidated. Platelet-activating factor (PAF) is one of the mediators involved in inflammatory tissue alterations associated with acute liver failure. In this study, alterations in blood PAF levels and the serum activity of PAF-acetylhydrolase (PAF-AH) were investigated over the time course of liver injury and regeneration induced by acetaminophen treatment in rats. The administration of a toxic dose of acetaminophen (3.5 g/kg) in rats caused acute hepatic injury, as evident by alterations of biochemical (serum enzymes: ALT, AST and ALP) and liver histopathological (degree of inflammation and apoptosis) indices between 20 and 40 h post-treatment. The hepatic damage was followed by liver regeneration, made evident by three independent indices ([3H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity and hepatocyte mitotic index), presenting a peak at 72 h. The PAF levels were elevated at 24 and 28 h, presenting a remarkable peak at 32 h post-treatment. PAF-AH activity presented different kinetics to that of PAF. The enzyme activity was relatively low at all time points examined before the rise in PAF activity, peaking later, at 72, 84 and 96 h. Our data demonstrate that PAF is involved in the pathogenesis of acute liver failure and in augmented compensatory liver tissue repair post-acetaminophen treatment. However, the putative role of PAF during liver toxicity and regeneration remains to be established.

Keywords: Acetaminophen (paracetamol); APAP; PAF; PAF-AH; Liver; Toxicity; Injury; Failure; Regeneration

Effect of ethane-1-hydroxy-1,1-bisphosphonate (EHBP) on endochondral ossification lesions induced by a lethal oral dose of uranyl nitrate by C. B. Bozal; A. B. Martinez; R. L. Cabrini; A. M. Ubios (pp. 475-481).

A 350 mg/kg body weight (b.w.) oral dose of uranyl nitrate (UN) caused 100% mortality in mice three days after administration, due to resulting kidney lesions. Mortality decreased 50% after an oral (o) or subcutaneous (sc) dose of bisodic etidronate (EHBP). Given that bone is also a target organ for uranium (U) in acute intoxication, the aim of this work was to study the effect of exposure to a lethal oral dose of UN on endochondral ossification, and the latter’s response to EHBP treatment. One hundred male Balb/c mice weighing 25 g were assigned to one of ten groups. Group I served as control. Group II received a lethal 350 mg/kg b.w. oral dose of UN by gavage. Groups III, IV, VII, and VIII received an equal dose of UN immediately followed by a single 500 mg/kg oral dose of EHBP in groups III and VII and a single 50 mg/kg subcutaneous dose of EHBP in groups IV and VIII. Groups V and IX only received a single 500 mg/kg oral dose of EHBP, and groups VI and X received a single 50 mg/kg subcutaneous dose of EHBP. The animals in groups II, III, IV, V, and VI were sacrificed 48 h after the onset of the experiment, whereas those in groups VII, VIII, IX, and X were killed at 14 days. Histologic and histomorphometric studies were performed on the femurs to determine growth cartilage width, bone volume, and metaphyseal bone activity. Our results showed that all growth cartilage and metaphyseal bone histomorphometric parameters were significantly lower in animals exposed to UN at 48 h than in controls. EHPB administration was found to prevent this condition at 48 h reaching similar values to those of controls. Although histomorphometric values did not reach control values at 14 days, they were higher than those of animals exposed to UN at 48 h not treated with EHBP. It is noteworthy that these values also decreased in animals only receiving EHBP at 14 days. Our results show that EHBP effectively ameliorates the adverse effects of a lethal dose of UN on endochondral ossification.

Keywords: Uranium exposure; Oral uranium; Bisodic etidronate; Endochondral ossification; Growth cartilage

Chemoprotective effects of captopril against cyclophosphamide-induced genotoxicity in mouse bone marrow cells by S. J. Hosseinimehr; M. Karami (pp. 482-486).

The protective effects of captopril (CAP) against toxicity induced by cyclophosphamide (CP) in mice were investigated using the micronucleus assay for anticlastogenic activity in mouse bone marrow cells and liver glutathione (GSH) content. A single intraperitoneal (i.p.) injection of CAP at 50, 100, and 200 mg/kg 1 h prior to cyclophosphamide (50 mg/kg) reduced the frequency of micronucleated polychromatic erythrocytes (MnPCEs). All three doses of CAP significantly reduced the frequency of MnPCEs in mouse bone marrow compared to the group treated with CP alone (P<0.0001–0.01). CP significantly depleted the GSH content in liver but the application of CAP at a dose of 100 mg/kg 1 h before CP treatment repleted the GSH content. CAP exhibited concentration-dependent antioxidant activity, scavenging >96% of the 1,1-diphenyl-2-picryl hydrazyl free radicals when used at a concentration of 0.2 mM. It appears that CAP, due to its antioxidant activity and by increasing GSH levels, can modulate the reduced cellular thiol content induced by CP and reduce the genotoxicity of CP in bone marrow cells.

Keywords: Captopril; Cyclophosphamide; Micronucleus; Chemoprotection; Glutathione

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Archives of Toxicology (v.79, #8)

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Archives of Toxicology (v.79, #8)