The effect of aromatic fluorine substitution on the nephrotoxicity and metabolism of N-(3,5-dichlorophenyl)succinimide in fischer 344 rats

Kellner-Weibel, Ginny; Nyarko, Alexander Kwadwo; Tchao, Ruy; Henesey, Caroline M.; Harvison, Peter J.

doi:10.1016/s0300-483x(96)03556-1

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…Incubation of DFPS with hepatocytes or kidney cells also revealed a pattern of biotransformation similar to NDPS (Kellner-Weibel et al, 1997). That is, hepatocytes converted DFPS to DFPSA, DFHS, 2-and 3-DFHSA, and DFHPSA, with DFPSA being the predominant metabolite (51%).…”

Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 90%

“…N-(3,5-Difluorophenyl)succinimide (DFPS) Unlike NDPS, DFPS does not induce nephrotoxicity in male Fischer 344 rats at ip doses up to 1 mmol/kg (Kellner-Weibel et al, 1997;Yang et al, 1987b). Kellner-Wiebel et al (1997) examined the biotransformation of DFPS and the nephrotoxic potential of DFPS metabolites to gain insight into reasons for why DFPS is the only N- (3,5dihalophenyl)succinimide that is a nonnephrotoxicant (Table 3).…”

Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 99%

“…Thus, DFPS and NDPS appear to exhibit similar biotransformation pathways. When evaluated for nephrotoxic potential at a dose of 1 mmol/kg (ip) in male Fischer 344 rats over 48 h, Kellner-Weibel et al (1997) found that neither DFPS nor its metabolites induced marked, irreversible nephrotoxicity. DFHS administration induced diuresis, elevated kidney weight, and decreased organic ion accumulation by renal cortical slices from treated animals, but did not elevate BUN concentration.…”

Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 99%

See 2 more Smart Citations

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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Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 90%

Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 99%

Section: Table 4 Comparative Minimal Nephrotoxic Doses Of Ndps and Imentioning

confidence: 99%

See 1 more Smart Citation

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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“…2-NDHSA and NDPSA were prepared by the methods of Kellner-Weibel et al (1997) and Fujinami et al (1972), respectively. All reagents were of the highest purity commercially available and were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

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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“…Due to health concerns related to its toxicity, NDPS is not widely used worldwide; it is mainly used in Asian countries, including China. NDPS has recently been proposed as a model compound for study of chemically induced kidney damage [18]. However, it is still not clear if NDPS has any antiandrogenic activity.…”

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confidence: 99%

The Antiandrogenic Activity of the Fungicide N-(3, 5-Dichlorophenyl) Succinimide in In Vivo and In Vitro Assays

Zhang

Zheng

et al. 2007

Journal of Reproduction and Development

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Abstract. Antiandrogens can cause reproductive disorders in humans and wild animals. In the present study, we tested whether the fungicide N-(3, 5-dichlorophenyl) succinimide (NDPS) acts as an antiandrogen using in vitro and in vivo assays. A transient transfection system based on luciferase activity was utilized for in vitro analysis of the antiandrogeic activity of NDPS. Hershberger assay was used to analyze the antiandrogenic activity of NDPS in rats. The expressions of the androgenresponsive genes testosterone-repressed prostatic message-2 (TRPM-2) and prostate specific binding protein polypeptide C3 (PBP C3) in the rat ventral prostate were measured using real-time PCR. Our results indicated that NDPS can block 5-dehydrotestosterone (DHT)-induced androgen receptor (AR) activity in transiently transfected HepG2 cells (-5 log M). In the Hershberger assay, the weights of the seminal vesicles and levator ani/bulbocavernosus muscles were significantly decreased (P<0.05) in all NDPS groups, and the weights of the ventral prostate, dorsolateral prostate, and Cowper's glands were significantly decreased (P<0.05) in the 100 and 200 mg/kg NDPS groups. NDPS only decreased (P<0.05) the expression of PBP C3 and had no effect on the level of TRPM-2 (P>0.05). In conclusion, NDPS is a moderate antiandrogen that elicits antiandrogenic effects at least partly by antagonizing AR and increasing the expression of PBP C3.

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The effect of aromatic fluorine substitution on the nephrotoxicity and metabolism of N-(3,5-dichlorophenyl)succinimide in fischer 344 rats

Cited by 9 publications

References 28 publications

Mobile Telephones and Cancer—a Review of Epidemiological Evidence

Mobile Telephones and Cancer—a Review of Epidemiological Evidence

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

The Antiandrogenic Activity of the Fungicide N-(3, 5-Dichlorophenyl) Succinimide in In Vivo and In Vitro Assays

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