Oral toxicity and metabolism of diuron (N-(3,4-dichlorophenyl)-N′,N′-dimethylurea) in rats and dogs

Hodge, Harold C.; Downs, William L.; Panner, B.S.; Smith, Douglas W.; Maynard, Elliott A.; Clayton, J. W.; Rhodes, Robert C.

doi:10.1016/s0015-6264(67)83153-5

Cited by 63 publications

(29 citation statements)

References 4 publications

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“…In electrospray ionization, all of the compound would not necessarily ionize, and, consequently, these metabolites would not be detected. In some dogs diuron was reported to be metabolized in vivo to phenolic compounds that are frequently excreted as sulfate and glucuronide conjugates (Hodge et al, 1967). Even if we were not able to detect any phase II metabolites, it is possible that the formation of "MS-invisible" metabolites could partially explain the rapid disappearances of both diuron and N-demethyldiuron, at least in dogs.…”

Section: Abass Et Almentioning

confidence: 73%

“…Diuron has been reported to be metabolized in vivo in rats, dogs (Hodge et al, 1967), and humans (Verheij et al, 1989;Van Boven et al, 1990) via demethylation, didemethylation, and hydroxylation. In addition, mouse liver microsomes metabolized diuron mainly to demethyldiuron (Suzuki and Casida, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…In metabolic studies of rats and dogs, N-(3,4-dichlorophenyl)urea was the predominant metabolite in the urine. Small amounts of N- (3,4-dichlorophenyl)-N-methylurea, 3,4-dichloroaniline, 3,4-dichlorophenol, and unchanged diuron were detected (Hodge et al, 1967).…”

mentioning

confidence: 99%

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Characterization of Diuron N-Demethylation by Mammalian Hepatic Microsomes and cDNA-Expressed Human Cytochrome P450 Enzymes

Abass

Reponen²,

Turpeinen³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Diuron, a widely used herbicide and antifouling biocide, has been shown to persist in the environment and contaminate drinking water. It has been characterized as a "known/likely" human carcinogen. Whereas its environmental transformation and toxicity have been extensively examined, its metabolic characteristics in mammalian livers have not been reported. This study was designed to investigate diuron biotransformation and disposition because metabolic routes, metabolizing enzymes, interactions, interspecies differences, and interindividual variability are important for risk assessment purposes. The only metabolic pathway detected by liquid chromatography/mass spectometry in human liver homogenates and seven types of mammalian liver microsomes including human was demethylation at the terminal nitrogen atom. No other phase I or phase II metabolites were observed. The rank order of N-demethyldiuron formation in liver microsomes based on intrinsic clearance (V max /K m ) was dog > monkey > rabbit > mouse > human > minipig > rat. All tested recombinant human cytochrome P450s (P450s) catalyzed diuron N-demethylation and the highest activities were possessed by CYP1A1, CYP1A2, CYP2C19, and CYP2D6. Relative contributions of human CYP1A2, CYP2C19, and CYP3A4 to hepatic diuron N-demethylation, based on average abundances of P450 enzymes in human liver microsomes, were approximately 60, 14, and 13%, respectively. Diuron inhibited relatively potently only CYP1A1/2 (IC 50 4 M). With human-derived and quantitative chemical-specific data, the uncertainty factors for animal to human differences and for human variability in toxicokinetics were within the range of the toxicokinetics default uncertainty/safety factors for chemical risk assessment.

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Section: Abass Et Almentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Characterization of Diuron N-Demethylation by Mammalian Hepatic Microsomes and cDNA-Expressed Human Cytochrome P450 Enzymes

Abass

Reponen²,

Turpeinen³

et al. 2007

Drug Metab Dispos

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“…Tissue levels of diuron were positively correlated with dosage. No apparent storage of diuron in tissues was noted (Hodge et al, 1967). In mammals, diuron is mainly metabolized by dealkylation of the urea methyl groups.…”

Section: Diuronmentioning

confidence: 96%

Phenylurea Herbicides

Liu

2010

Hayes' Handbook of Pesticide Toxicology

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“…The potential of linuron to accumulate in aquatic and terrestrial systems is comparatively low (Kempson-Jones 13 Hanel 1979, Zahnow & Rigglem.an 1980, Maier-Bode & Hartel 1981. Although there is only limited risk of bioaccumulation in mammals (Hodge et al 1968), with highest values in faeces and urine as well as in adipose tissues and the liver (Maier-Bode & Hartel 1981), linuron was included in a list of 129 chemicals to be given priority in future investigations (Malle 1984). Whereas in older reports the mutagenic and carcinogenic potential of linuron appeared ambiguous (Hodge e t al.…”

Section: Introductionmentioning

confidence: 99%

Cytopathology of liver and kidney in rainbow trout Oncorhynchus mykiss after long-term exposure to sublethal concentrations of linuron

Oulmi¹,

Negele²,

Braunbeck³

1995

Dis. Aquat. Org.

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Hepatic and renal cytopathological alterations in fingerl~ng rainbow trout Oncorhynchus mykiss following 5 \vk exposure to 30, 120, and 240 pg I -' linuron [3(3,4-dichloropheny1)-l-methoxy-lmethylurea] were studied by electron microscopy. Ultrastructural alterations were detected in liver and kidney at 230 pg l.', 2 orders of magnitude below conventional LCo. The response suggested a doseresponse relationship with a change from adaptive to degenerative features at 120 pg I-' Hepatocyte changes included: stimulation of mitosis; segmentation of nuclei; partial reorganization of heterochromatin; multiplication of nucleoli; fractionation, vesiculation and transformation of rough endoplasmic reticulum (RER) into myelinated bodies; induction of smooth endoplasmic reticulum; moderate steatosis; apparent proliferation of mitochondria, peroxlsomes, Golgi fields and lysosomal elements; depletion of glycogen; perisinusoidal lipid accumulat~on; elevated rate of hepatocytes in various stages of necrosis; infiltration and increased phagocytic activity of macrophages. Reactions of renal tubular cells were differentiated in different nephron segments. Major alterations by site in kidney were (1) renal corpuscle: lobulation of podocyte nuclei; (2) proximal segment I: elevated heterogeneity of all cell components, increased heterochromatin and nuclear size, rearrangement of RER, proliferation of Golgi fields, novel lysosomal elements, decreased mitochondria and lysosomes at 240 1-19 I-'; (3) proximal segment 11: nuclear lobulation, binucleated cells, proliferation of lysosomes and peroxisomes (lower concentrations), decreased peroxisomes and mitochondria (240 pg I-'), crystalline inclusions in lysosomal matrix, fragmentation, degranulation and circular arrangement of RER; (4) distal segment: induction of giant mitochondria with longitudinal crystalline inclusions, atypical lysosomes with long crystalline matrix inclusions, and augmentation of various lysosomal elements. Comparison of linuroninduced cellular alterations with cytopathological effects by potential linuron breakdown products, namely 4-chloroaniline and 3,4-dichloroaniline, revealed a high degree of s~milarity of cytopathological phenomena, indicating that part of the changes observed after linuron exposure might well be due to the action of linuron metabolites.

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Oral toxicity and metabolism of diuron (N-(3,4-dichlorophenyl)-N′,N′-dimethylurea) in rats and dogs

Cited by 63 publications

References 4 publications

Characterization of Diuron N-Demethylation by Mammalian Hepatic Microsomes and cDNA-Expressed Human Cytochrome P450 Enzymes

Characterization of Diuron N-Demethylation by Mammalian Hepatic Microsomes and cDNA-Expressed Human Cytochrome P450 Enzymes

Phenylurea Herbicides

Cytopathology of liver and kidney in rainbow trout Oncorhynchus mykiss after long-term exposure to sublethal concentrations of linuron

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