Document Detail

Cytotoxic and porphyrinogenic effects of diphenyl ethers in cultured rat hepatocytes: chlornitrofen (CNP), CNP-amino, chlomethoxyfen and bifenox.
MedLine Citation:
PMID:  10069484     Owner:  NLM     Status:  MEDLINE    
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.
H Jinno; N Hatakeyama; N Hanioka; R Yoda; T Nishimura; M Ando
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
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:
Created Date:  1999-03-18     Completed Date:  1999-03-18     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8207483     Medline TA:  Food Chem Toxicol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  69-74     Citation Subset:  IM    
Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan.
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MeSH Terms
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
Oxidoreductases / drug effects,  metabolism
Oxidoreductases Acting on CH-CH Group Donors*
Phenyl Ethers / toxicity*
Protoporphyrinogen Oxidase
Rats, Wistar
Reg. No./Substance:
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 Oxidase

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