| Cytotoxic and porphyrinogenic effects of diphenyl ethers in cultured rat hepatocytes: chlornitrofen (CNP), CNP-amino, chlomethoxyfen and bifenox. | |
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MedLine Citation:
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PMID: 10069484 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We studied the cytotoxic and porphyrinogenic effects of four diphenyl ethers (DPEs), chlornitrofen (CNP), CNP-amino, chlomethoxyfen and bifenox, in rat hepatocytes cultured on Matrigel. Cytotoxicity was determined as a decrease in viability measured by the release of lactate dehydrogenase. Of the DPEs examined. CNP-amino was the most cytotoxic, with an LC50 value of 0.36 mM (95% confidence interval, 0.33-0.40 mM). CNP also reduced the viability in a concentration-dependent manner at the concentrations of 0.50 mM or above. In contrast, no concentration-dependent decrease in viability was observed in the chlomethoxyfen- and bifenox-treated hepatocytes at the concentrations up to 1.0 mM. To identify the enzyme involved in the metabolic activation of CNP-amino, inhibition studies were carried out using SKF 525-A (0.050 mM) and methimazole (1.0 mM). SKF 525-A, a cytochrome P450 inhibitor. quickened the onset of cell killing by CNP-amino, while methimazole, an inhibitor of flavin-containing monooxygenase (FMO), partially suppressed the cytotoxicity of CNP-amino. These results suggest that FMO plays an important role in the cytotoxicity induced by CNP-amino, while cytochrome P450 participates in the detoxification, possibly via the ring-hydroxylation. The maximum porphyrin accumulation was observed at 0.13 mM for chlomethoxyfen (18-fold) and at 0.25 mM for CNP and bifenox (17- and 21-fold, respectively). In contrast to these DPEs, the porphyrinogenic effect of CNP-amino was weak, with the maximum accumulation at 0.13 mM (at least fivefold). The predominant species was protoporphyrin IX in all of the DPE-treated cultures. These results suggest that all of the DPEs examined, possibly including CNP-amino, inhibit protoporphyrinogen oxidase, resulting in the accumulation of protoporphyrin IX. |
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Authors:
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H Jinno; N Hatakeyama; N Hanioka; R Yoda; T Nishimura; M Ando |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Volume: 37 ISSN: 0278-6915 ISO Abbreviation: Food Chem. Toxicol. Publication Date: 1999 Jan |
Date Detail:
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Created Date: 1999-03-18 Completed Date: 1999-03-18 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8207483 Medline TA: Food Chem Toxicol Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 69-74 Citation Subset: IM |
Affiliation:
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Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Survival / drug effects Cells, Cultured Chromatography, High Pressure Liquid Dose-Response Relationship, Drug Heme / biosynthesis* Herbicides / toxicity* Lethal Dose 50 Liver / cytology, drug effects*, enzymology Male Oxidoreductases / drug effects, metabolism Oxidoreductases Acting on CH-CH Group Donors* Phenyl Ethers / toxicity* Protoporphyrinogen Oxidase Rats Rats, Wistar |
| Chemical | |
Reg. No./Substance:
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0/Herbicides; 0/Phenyl Ethers; 14875-96-8/Heme; 1836-77-7/2,4,6-trichlorophenyl 4-nitrophenyl ether; 32861-85-1/chlormethoxynil; 42576-02-3/bifenox; EC 1.-/Oxidoreductases; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC 1.3.3.4/Protoporphyrinogen Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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