Lack of human relevance for procymidone's developmental toxicity attributable to species difference in its kinetics and metabolism.

The agricultural fungicide procymidone can cause external genitalia abnormalities in rats but not monkeys or rabbits. To investigate the relevance of developmental findings in rats to humans, we conducted plasma protein binding studies, metabolism (biotransformation) studies using liver S9 fractions and hepatocytes, and metabolism and excretion studies using chimeric mice with humanized hepatocytes. On the basis of these results, we concluded that the metabolic and excretion profiles of procymidone in humans are similar to those in monkeys and rabbits but differ from those in rats.

Species differences in the developmental toxicity of procymidone-Placental transfer of procymidone in pregnant rats, rabbits, and monkeys.

To clarify species differences in the developmental toxicity of procymidone (Sumilex®, a fungicide for agricultural use), placental transfer studies were conducted using C-labeled procymidone in pregnant rats, rabbits, and monkeys. These studies demonstrated that maternal-to-fetal transfer of the parent compound and its hydroxylated metabolite, which are both weak anti-androgenic agents, occurred more easily than that of other metabolites, with much higher absolute concentrations achieved in the fetal circulation of rats than of rabbits or monkeys. Notably, in rats, the fetal plasma concentration of the hydroxylated metabolite was higher than that of procymidone, especially after repeated oral administration of procymidone.

Flumioxazin metabolism in pregnant animals and cell-based protoporphyrinogen IX oxidase (PPO) inhibition assay of fetal metabolites in various animal species to elucidate the mechanism of the rat-specific developmental toxicity.

Flumioxazin, an N-phenylimide herbicide, inhibits protoporphyrinogen oxidase (PPO), a key enzyme in heme biosynthesis in mammals, and causes rat-specific developmental toxicity. The mechanism has mainly been clarified, but no research has yet focused on the contribution of its metabolites. We therefore conducted in vivo metabolism studies in pregnant rats and rabbits, and found 6 major known metabolites in excreta.

Metabolism of metofluthrin in rats: II. Excretion, distribution and amount of metabolites.

1. C-Labelled E/Z isomers of a synthetic pyrethroid metofluthrin ((E/Z)-(1 R,3 R)-2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate, abbreviated as RTE/RTZ, respectively) were used for rat metabolism studies. C-RTE or RTZ labelled at the carbonyl-carbon [acid-C] or the methoxymethylbenzyl-α-carbon [alcohol-C] was administered orally to rats at 1 and 20 mg/kg.

Metabolism of metofluthrin in rats: I. Identification of metabolites.

1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. 2.

Metabolism of (Z)-(1R,3R)-Profluthrin in Rats.

When [benzyl-α-(14)C]-labeled (Z)-(1R,3R)-profluthrin (2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1R,3R)-2,2-dimethyl-3-(prop-1-enyl) cyclopropanecarboxylate, a newly developed pyrethroid) was administered orally to rats at 1 mg/kg, around 70% was absorbed, metabolized, and mainly excreted into urine within 48 h. Radioactivity in plasma reached Cmax at 6-8 h, and decreased (half-life; 37-52 h). A similar tendency was observed also in tissues.

Comparison of cytokine profiles in bronchoalveolar lavage fluid of mice exposed to respiratory and contact sensitizers.

Respiratory sensitization to certain low molecular weight chemicals is a big concern for workers, but unfortunately there are no validated animal models to allow identification of sensitizing chemicals in the environment. In the present study, dermally sensitized and intratracheally challenged mice were used to investigate effective indicators of respiratory sensitizers. Changes in levels of total serum IgE and nine cytokines (G-CSF, IL-4, IL-5, IL-6, IL-12(p70), IL-13, IFN-γ, MCP-1 and TNF-α) in bronchoalveolar lavage fluid (BALF) were analyzed in BALB/c mice exposed to respiratory sensitizers (phthalic anhydride (PA); diphenylmethane-4,4'-diisocyanate (MDI); toluene diisocyanate (TDI); chloramine-T (CH); and piperazine (PI)) or contact sensitizers (2,4-dinitrochlorobenzene (DNCB); and oxazolone (OXA)).

Biotransformation and enzymatic reactions of synthetic pyrethroids in mammals.

Synthetic pyrethroids, a major insecticide group, are used worldwide for controlling indoor and agricultural pests. Extensive mammalian metabolism studies have been carried out since the late 1960s, and major metabolic reactions have been found to be oxidation of the acid or alcohol moiety, ester cleavage, and conjugation reactions. In addition, various conjugation reactions occur in mammals, forming hydrophilic and lipophilic conjugates.

In vitro metabolism of trans-permethrin and its major metabolites, PBalc and PBacid, in humans.

To estimate the metabolic profile of trans-permethrin in humans, a comparison of the in vitro metabolism of trans-permethrin in humans and rats was conducted using hepatic microsomes, and cytochrome P450 and UDP-glucuronyltransferase isoforms, which catalyze the metabolism of 3-phenoxybenzyl alcohol (PBalc) and 3-phenoxybenzoic acid (PBacid), respectively. In humans and rats, the major metabolic reaction of trans-permethrin in microsomal incubations was the cleavage of ester linkage to give PBalc, followed by oxidation to 4'-OH-PBalc, 4'-OH-PBacid, and PBacid. As to 4'-hydroxylation of PBalc, several CYPs were able to catalyze the reaction, and CYP2E1 was identified as a predominant isoform.

Metabolism of 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether (pyridalyl) in rats after repeated oral administration and a simple physiologically based pharmacokinetic modeling in brown and white adipose tissues.

Male and female Sprague-Dawley rats received repeated oral administration of 14C-2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3- [5-(trifluoromethyl)-2-pyridyloxy]propyl ether (14C-pyridalyl) at 5 mg/kg/day for 14 consecutive days, and 14C excretion, 14C concentration in tissues, and the metabolic fate were determined. Most 14C was excreted into feces. The 14C concentrations in the blood and tissues attained steady-state levels at days 6 to 10, whereas those in white adipose tissues increased until day 14.

Metabolism of pyridalyl in rats: excretion, distribution, and biotransformation of dichloropropenyl-labeled pyridalyl.

Metabolism of pyridalyl [2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether] labeled at position 2 of the dichloropropenyl group with 14C was investigated after single oral administration to male and female rats at 5 and 500 mg/kg. Absorbed 14C was excreted into feces (68-79%), urine (8-14%), and expired air (6-10%) in all of the groups. Regarding 14C-tissue residues on the seventh day after administration, fat showed the highest levels at 0.

Metabolism of pyridalyl in rats.

Metabolism of pyridalyl [2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether] was examined in male and female Sprague-Dawley rats. After a single oral administration of [dichlorophenyl-(14)C]pyridalyl at 5 or 500 mg/kg, the (14)C concentration in blood reached maxima at 2 to 10 h and then decreased rapidly with a biological half-life of approximately 11 to 12 h. (14)C concentrations in liver, fat, adrenal gland, and spleen were relatively high at a low dose, reaching 2.

Metabolism of flufenpyr-ethyl in rats and mice.

The metabolism of flufenpyr-ethyl [ethyl 2-chloro-5-[1,6-dihydro-5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1-yl]-4-fluorophenoxyacetate] was examined in rats and mice. [Phenyl-(14)C]flufenpyr-ethyl was administered to rats and mice as a single oral dose at a level of 500 mg/kg, and (14)C-excretion was examined. Total (14)C-recoveries within 7 days after administration were 93.

Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes.

High doses of Metofluthrin (MTF) have been shown to produce liver tumours in rats by a mode of action (MOA) involving activation of the constitutive androstane receptor leading to liver hypertrophy, induction of cytochrome P450 (CYP) forms and increased cell proliferation. The aim of this study was to compare the effects of MTF with those of the known rodent liver tumour promoter phenobarbital (PB) on the induction CYP2B forms and replicative DNA synthesis in cultured rat and human hepatocytes. Treatment with 50 microM MTF and 50 microM PB for 72 h increased CYP2B1 mRNA levels in male Wistar rat hepatocytes and CYP2B6 mRNA levels in human hepatocytes.

Metabolism of N-[(R)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (Delaus, S-2900) and its isomer, N-[(S)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (S-2900S), in rats. 1. Identification of metabolites in feces and urine.

Rats were orally dosed with a 1:1 diastereomixture of N-[(R)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (Delaus, S-2900) and N-[(S)-1-(2,4-dichlorophenyl)ethyl]-2-cyano-3,3-dimethylbutanamide (S-2900S), both labeled with 14C, at 200 mg/kg/day for 5 consecutive days, and 16 metabolites in urine and feces were purified by a combination of several chromatographic techniques. The chemical structures of all isolated metabolites were identified by spectroanalyses (NMR and MS). Several of them were unique decyanated and/or cyclic compounds (lactone, imide, cyclic amide, cyclic imino ether forms).

Metabolism of diethofencarb (isopropyl 3,4-diethoxyphenylcarbamate) in rats: identification of metabolites in urine.

Rats were orally given a diethofencarb (isopropyl 3,4-diethoxyphenylcarbamate) labeled with (14)C, at 300 mg/kg/day, for 4 consecutive days, and 11 metabolites in urine were purified by a combination of several chromatographic techniques. The chemical structures of all isolated metabolites were identified by spectroanalyses (NMR and MS). Ten of them were newly identified forms.