Effect of microsomal enzyme activity modulation on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity

Rankin, Gary O.; Yang, David J.; Richmond, Cathy D.; Teets, Vonda J.; Wang, R.T.; Brown, Patrick I.

doi:10.1016/0300-483x(87)90018-7

Cited by 49 publications

(8 citation statements)

References 13 publications

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“…In agreement with Rankin et al (1987), we found that PB pretreatment potentiated NDPS (0.2 mmol/kg) nephrotoxicity in rats. PB is an inducer of the P450 2B1/2B2 isozymes in rat liver (Guengerich et al, 1982), but has no effect on rat renal P450 (Tarloff et al, 1990).…”

Section: Discussionsupporting

confidence: 78%

“…Aside from some diuresis and proteinuria, we found little evidence of kidney damage in rats that received a nontoxic dose (0.2 mmol/kg) of NDPS following 3-MC pretreatment. These results are somewhat different than those reported by Rankin et al (1987) and may be due to the fact that we used a different induction protocol (three doses of 3-MC instead of one). Pretreatment with INH, which, like acetone, is an inducer of P450 2E1 (Ryan et al, 1985;Thomas et al, 1987), also failed to potentiate NDPS nephrotoxicity.…”

Section: Discussioncontrasting

confidence: 56%

“…Since the 3-MC-inducible isozymes have no apparent role in the metabolic activation of NDPS, these results also suggest that the effects seen with ARO (above) may be due to the ability of this compound to increase levels of the PBinducible isozymes (i.e., 2B1/2B2) of P450. Rankin et al (1987) demonstrated that the P450 inhibitors cobalt chloride and piperonyl butoxide inhibited NDPS-induced nephrotoxicity. We wanted to evaluate the ability of ABT, a selective, suicide inhibitor of P450 (Mugford et al, 1992), to prevent NDPS metabolism and nephrotoxicity in rats.…”

Section: Discussionmentioning

confidence: 99%

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Cytochrome P450-Mediated Metabolism and Nephrotoxicity of N-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats

1997

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The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Previous studies have suggested that oxidative hepatic biotransformation is required for the induction of kidney damage. The experiments described in this paper were designed to further investigate the relationship between NDPS metabolism and nephrotoxicity using various modulators of cytochrome P450 activity. Male Fischer 344 rats were pretreated with the P450 inducers Aroclor 1254 (ARO), isoniazid (INH), 3-methylcholanthrene (3-MC), and phenobarbital (PB), or the P450 inhibitor 1-aminobenzotriazole (ABT). Control animals received vehicle only. NDPS metabolism was investigated using hepatocytes isolated from the various treatment groups. Separate experiments were also conducted to evaluate the effects of these pretreatments on NDPS-induced nephrotoxicity in rats. PB and ARO enhanced formation of the known nephrotoxic NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide, N-(3,5-dichlorophenyl>2-hydroxysuccinamic acid, and iV-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid, by the hepatocytes. In contrast, ABT inhibited formation of the nephrotoxic metabolites, whereas INH and 3-MC did not alter NDPS biotransformation. NDPS-induced renal damage was potentiated by pretreating the rats with PB or ARO and was attenuated by ABT. Compared with control animals, toxicity was unaffected by INH or 3-MC pretreatments. Thus, there was a correlation between pretreatments that induce P450-mediated NDPS metabolism and the effects that these compounds have on NDPS-induced nephrotoxicity. The data indicate that specific P450 isozymes metabolize NDPS to its hydroxylated products and suggest that these metabolites mediate the nephrotoxicity induced by NDPS. © 1997 Sodtty of To iV-(3,5-Dichlorophenyl)succinimide (NDPS, Fig.

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Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

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Cytochrome P450-Mediated Metabolism and Nephrotoxicity of N-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats

1997

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“…Rankin et al (1987a) found that pretreatment with phenobarbital potentiated NDPS nephrotoxicity in rats. Phenobarbital is a classical inducer of the CYP2B subfamily, but also has the ability to induce CYP3A4 (Omiecinski et al, 1999).…”

Section: N-(35-dichlorophenyl)malonamic Acid (Dma) It Was Also Detementioning

confidence: 97%

Mobile Telephones and Cancer—a Review of Epidemiological Evidence

Kundi

Mild²,

Hardell

et al. 2004

Journal of Toxicology and Environmental Health, Part B

135

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There is considerable public concern about possible long-term adverse health effects of mobile phones. While there is scientific controversy about long-term health effects of high-frequency electromagnetic fields lasting for at least 50 yr, the rise and success of mobile telecommunication made it necessary to investigate the problem more comprehensively and assess the possible risk cautiously because never before in history has a substantial proportion of the population been exposed to microwaves in the near field and at comparably high levels. Because the mostly localized exposure target region is the head, most epidemiological studies focus on brain tumors. Overall nine epidemiological studies have been published, four from the United States, two from Sweden, and one each from Denmark, Finland, and Germany. Seven studies were mainly on brain tumors, with one investigating in addition to brain tumors salivary gland cancer and another cancer of the hematopoietic and lymphatic tissues, and one examining intraocular melanoma. All studies have some methodological deficiencies: (1) too short duration of mobile phone use to be helpful in risk assessment, (2) exposure was not rigorously determined, and (3) there is a possibility of recall and response error in some studies. Nevertheless, all studies approaching reasonable latencies found an increased cancer risk associated with mobile phone use. Estimates of relative risk in these studies vary between 1.3 and 4.6 with highest overall risk for acoustic neuroma (3.5) and uveal melanoma (4.2), and there is evidence for enhanced cancer risk with increasing latency and duration of mobile phone use.

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“…Glucuronide/sulfate and glutathione-derived conjugates of 2-/3-NDHSA and NDPS/NDPSA, respectively, have also been reported (Cui et al, 2005). Both phase I and II metabolic pathways may be involved in the formation of a nephrotoxic species from NDPS (Rankin et al, 1987;Nyarko et al, 1997; Hong et al, 1999a,b;Cui et al, 2005). Using liquid chromatography-MS/MS (Cui et al, 2005), we tentatively identified two novel amino-derived metabolites of NDPS, N-(3,5-dichlorophenyl)-2-aminosuccinamic acid (2-NDASA) and its N-acetylated derivative (N-acetyl-2-NDASA).…”

Section: Introductionmentioning

confidence: 98%

Transamination in the Metabolism of the Nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in Rats

Cui

Rankin²,

Harvison³

2005

Drug Metabolism and Disposition

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ABSTRACT:The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Due to the involvement of NDPS metabolism in its mechanism of toxicity, the detailed biotransformation of 14 C-NDPS in rats was previously evaluated using highperformance liquid chromatography-electrospray ionization-mass spectrometry. In the present report, we describe the identification of two novel amino metabolites of NDPS, which were present in significant amounts in rat kidney tissues. Using liquid chromatography-tandem mass spectrometry and synthetic standards, the two metabolites were identified as N-(3,5-dichlorophenyl)-2-aminosuccinamic acid (2-NDASA) and its N-acetylated derivative (Nacetyl-2-NDASA). The mechanism of formation of 2-NDASA was studied in vitro. Incubations were carried out in rat liver and kidney cytosols using the major oxidative metabolite of NDPS, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, as the substrate. Formation of 2-NDASA in vitro was confirmed using mass spectrometry. Inhibitors of alcohol dehydrogenase (4-methylpyrazole) and aldehyde dehydrogenase (disulfiram) reduced 2-NDASA formation by 40 to 50%. Menadione (an inhibitor of aldehyde oxidase) and quercetin (an inhibitor of carbonyl reductase) did not show any effects. (Aminooxy)acetic acid, an inhibitor of pyridoxal 5-phosphate-containing enzymes such as aminotransferases, almost completely abolished the formation of 2-NDASA. Using liquid chromatography-mass spectrometry, the transamination mechanism was further supported by the incorporation of a 15 N-amino group in 2-NDASA when 15 N-glutamic acid was included in the incubation mixture. Results from these studies show that transamination is a metabolic pathway in the clearance of NDPS in rats, and that cytosolic dehydrogenases and aminotransferases may be involved in this process. succinimide (NDPS; Fig. 1) was originally synthesized as an agricultural antifungal agent (Fujinami et al., 1972). In subsequent testing, NDPS was shown to be nephrotoxic in male rats at doses Ն0.4 mmol/kg following acute administration (Rankin, 1982;Rankin et al., 1985). Although not widely used, NDPS remains on the market as an agricultural fungicide, and it has been studied extensively as a model compound for chemically induced kidney damage (Rankin, 2004).Studies in rats have shown that NDPS is well absorbed, widely distributed (highest in kidney), and rapidly eliminated, mainly as metabolites in urine (Ohkawa et al., 1974;Griffin and Harvison, 1998). The major in vivo metabolites of NDPS are N- (3,5-dichlorophenyl)succinamic acid (NDPSA), N-(3,5-dichlorophenyl)-2-and 3-hydroxysuccinamic acids (2-and 3-NDHSA), and N-(3,5-dichlorophenyl)malonamic acid (Ohkawa et al., 1974;Griffin and Harvison, 1998). Glucuronide/sulfate and glutathione-derived conjugates of 2-/3-NDHSA and NDPS/NDPSA, respectively, have also been reported (Cui et al., 2005). Both phase I and II metabolic pathways may be involved in the formation of a nephrotoxic species from NDPS (Rankin et al., 1987;Nyarko et al., 1997; Ho...

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Effect of microsomal enzyme activity modulation on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity

Cited by 49 publications

References 13 publications

Cytochrome P450-Mediated Metabolism and Nephrotoxicity of N-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats

Cytochrome P450-Mediated Metabolism and Nephrotoxicity of N-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats

Mobile Telephones and Cancer—a Review of Epidemiological Evidence

Transamination in the Metabolism of the Nephrotoxicant N-(3,5-Dichlorophenyl)succinimide in Rats

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