Chemically Induced Nephrotoxicity: Role of Metabolic Activation

Rush, Glenn F.; Smith, Jacqueline H.; Newton, John F.; Hook, Jerry B.; Berndt, William O.

doi:10.3109/10408448409034079

Cited by 108 publications

(24 citation statements)

References 219 publications

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“…The increased susceptibility of kidney function to amphotericin B may result from the fact that the activities of renal mixed function oxidases are usually less than those of these enzymes in the liver. For exam ple, the renal cytochrome P450 concentration is generally only 10-20% that of the liver [ 18], This may explain the results of our earlier study showing no adverse effects of amphoter icin B on hepatic cytochrome P450 and anti pyrine clearance following enzyme induction by phénobarbital [6], In summary this study demonstrates that amphotericin B treatment for 4 days inhibits several microsomal enzymes and antipyrine clearance in rats. From the results it seems possible that amphotericin B affects hepatic metabolic function by inhibition of certain steps in protein synthesis.…”

Section: Discussionsupporting

confidence: 69%

Influence of Amphotericin B Treatment Duration on Hepatic Microsomal Enzyme Function in Rats

Inselmann¹,

Voss²,

Kunigk

et al. 1997

Pharmacology

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The influence of amphotericin B on various cytochrome P450-dependent mixed-function oxidases, antipyrine clearance and glucose-6-phosphatase was investigated in rats treated daily with deoxycholate amphotericin B (3 mg/kg body weight, intravenously) either for 1 or 4 days. Enzyme activity was measured ex vivo in hepatic microsomes. Following amphotericin B plus deoxycholate application for 1 day, ethoxycoumarin-O-deethylase activity decreased significantly whereas microsomal cytochrome P450 concentration, cytochrome c reductase activity, antipyrine clearance and glucose-6-phosphatase activity did not change significantly. In contrast, following application of amphotericin B plus deoxycholate for 4 days the cytochrome P450 concentration was reduced by 50% (p < 0.05) as well as ethoxycoumarin-O-deethylase activity, antipyrine clearance and glucose-6-phosphatase activity: ethoxycoumarin-O-deethylase 232 ± 68 pmol/ mg/min, control 442 ± 99 pmol/mg/min (p < 0.01); antipyrine clearance 0.56 ± 0.21 ml/min, control 0.96 ± 0.18 ml/min (p < 0.01), and glucose-6-phosphatase 193 ± 28 mU/mg, control 351 ± 95 mU/mg (p < 0.05). Cytochrome c reductase activity did not decrease significantly. Besides an increase in cytochrome c reductase activity, sodium deoxycholate (a vehicle of amphotericin B) alone induced no significant changes. Microsomal protein related to liver wet weight was significantly reduced by 50% (p < 0.01) only in animals treated for 4 days with amphotericin B plus deoxycholate. The results show that a 1-day treatment of rats with amphotericin B decreases ethoxycoumarin-O-deethylase activity, whereas the hepatic microsomal cytochrome P450 content, cytochrome c reductase and glucose-6-phosphatase activity did not change. Amphotericin B given for 4 days significantly decreases hepatic microsomal enzyme function. The inhibitory effect of amphotericin B on hepatic cytochrome P450 may be due to inhibition of hepatic protein synthesis.

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Section: Discussionsupporting

confidence: 69%

Influence of Amphotericin B Treatment Duration on Hepatic Microsomal Enzyme Function in Rats

Inselmann¹,

Voss²,

Kunigk

et al. 1997

Pharmacology

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“…This may in turn lead to the depletion of intracellular GSH resulting in cellular injury. 35 The biochemical analysis of this study is confirmed by the histopathological examination of the renal tissue, where GM groups demonstrated extensive hemorrhage, focal fibrosis, necrotic changes, and infiltration ( Figure 3). These results are in accordance with the findings reported by Soliman et al 28 However, coadministration of GTE with GM in Group 4 revealed renoprotective effects and showed only mild infiltration (Figure 3).…”

Section: Discussionmentioning

confidence: 61%

Amelioration of gentamicin nephrotoxicity by green tea extract in uninephrectomized rats as a model of progressive renal failure

Salem

Kamel

et al. 2010

Renal Failure

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Rationale: Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. This study investigates whether green tea extract (GTE), an antioxidant, could ameliorate the nephrotoxic effect of GM in uninephrectomized rats. Objectives: The right kidneys of 40 rats were surgically removed and 1 week later the animals were divided into four groups (n = 10). Group 1 served as control, Group 2 as GTE group, Group 3 as GM group, and Group 4 as GM+GTE group. Kidney function, inflammatory cytokine TNF-a, oxidant and antioxidant parameters of renal tissue, as well as histopathological studies were assessed. Main findings: Injecting uninephrectomized rats with GM induced renal dysfunction as shown by significant elevations in serum creatinine and urea. Serum TNF-a and oxidative stress parameters (superoxide anion and lipid peroxides) were also significantly increased. On the contrary, antioxidative parameters [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)] were significantly decreased. Histopathological examination of renal tissue illustrated features of degeneration, marked cellular infiltration, tubular dilatation, and varying degrees of necrosis. GTE given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and TNF-a were almost normalized in the GM+GTE group. The oxidative stress parameters were significantly decreased and the antioxidative parameters were significantly increased. Conclusion: GTE ameliorates GM-induced nephrotoxicity and oxidative damage by improving antioxidant defense and tissue integrity. Further human studies are necessary to demonstrate the antioxidant effects of GTE on renal diseases. Nevertheless, green tea (GT) may offer an inexpensive, nontoxic, and effective intervention strategy in subjects with a risk for GM-induced nephrotoxicity.

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“…The presence of a cytochrome P450 system in the kidney cortex and a prostaglandin endoperoxidase in the medulla may account for the difference in the level of damage in different regions of the kidney. 35 Similarly, a potent anticancer drug, cisplatin caused morphological damage that was more severe in the renal cortex than in the medulla, and these effects were also shown to be prevented by administration of melatonin. 39 In our study, CCl 4 -intoxicated rats showed a significant elevation in the relative kidney weight compared to that of controls.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Numerous experimental studies indicate that CCl 4 causes tissue damage in many organs, although mainly liver, and it causes changes in various blood biochemical parameters. 1,6,9,10,33 Since the kidney has an affinity for CCl 4 1 and contains cytochrome P450 predominantly in the cortex, 1,34,35 CCl 4 is likely to contribute to nephrotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Reduction of carbon tetrachloride‐induced nephropathy by melatonin administration

Ögetürk

Kuş

Kavakli

et al. 2004

Cell Biochemistry & Function

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The aim of this study was to investigate possible protective effects of melatonin on carbon tetrachloride (CCl4)-induced renal damage in rats. A total of 24 animals were divided into three equal groups: the control rats received pure olive oil subcutaneously, rats in the second group were injected with CCl4 (0.5 ml kg-1, s.c. in olive oil) and rats in the third group were injected with CCl4 (0.5 ml kg-1) plus melatonin (25 mg kg-1, s.c. in 10% ethanol) every other day for 1 month. At the end of the experimental period, the animals were sacrificed and blood samples were collected. The kidneys were removed and weighed. Urea and creatinine levels were determined in blood samples. Histopathological examination of the kidney was performed using light microscopic methods. Administration of CCl4 significantly increased relative kidney weight (g per 100 g body weight) and decreased serum urea levels compared to controls (p<0.01). Melatonin treatment significantly (p<0.01) reduced relative kidney weight, and it produced a statistically equal (p=0.268) relative weight with the kidneys of control rats. CCl4 administration alone also caused histopathologically prominent damage in the kidney compared to the control group. Glomerular and tubular degeneration, interstitial mononuclear cell infiltration and fibrosis, vascular congestion around the tubules, and interstitial haemorrhage in perivascular areas were observed in the renal cortex and cortico-medullary border. However, the affect of CCl4 on the medulla was limited. Melatonin provided protection against CCl4-induced renal toxicity as was evident by histopathological evaluation. In view of the present findings, it is suggested that melatonin protects kidneys against CCl4 toxicity.

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Chemically Induced Nephrotoxicity: Role of Metabolic Activation

Cited by 108 publications

References 219 publications

Influence of Amphotericin B Treatment Duration on Hepatic Microsomal Enzyme Function in Rats

Influence of Amphotericin B Treatment Duration on Hepatic Microsomal Enzyme Function in Rats

Amelioration of gentamicin nephrotoxicity by green tea extract in uninephrectomized rats as a model of progressive renal failure

Reduction of carbon tetrachloride‐induced nephropathy by melatonin administration

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