- Human flavin-containing monooxygenase 1 and its long-sought hydroperoxyflavin intermediate
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Out of the five isoforms of human flavin-containing monooxygenase (hFMO), FMO1 and FMO3 are the most relevant to Phase I drug metabolism. They are involved in the oxygenation of xenobiotics including drugs and pesticides using NADPH and FAD as cofactors. Majority of the characterization of these enzymes has involved hFMO3, where intermediates of its catalytic cycle have been described. On the other hand, research efforts have so far failed in capturing the same key intermediate that is responsible for the monooxygenation activity of hFMO1. In this work we demonstrate spectrophotometrically the formation of a highly stable C4a-hydroperoxyflavin intermediate of hFMO1 upon reduction by NADPH and in the presence of O2. The measured half-life of this flavin intermediate revealed it to be stable and not fully re-oxidized even after 30 min at 15 °C in the absence of substrate, the highest stability ever observed for a human FMO. In addition, the uncoupling reactions of hFMO1 show that this enzyme is 2O2 with no observable superoxide as confirmed by EPR spin trapping experiments. This behaviour is different from hFMO3, that is shown to form both H2O2 and superoxide anion radical as a result of ~50% uncoupling. These data are consistent with the higher stability of the hFMO1 intermediate in comparison to hFMO3. Taken together, these data demonstrate the different behaviours of these two closely related enzymes with consequences for drug metabolism as well as possible toxicity due to reactive oxygen species.
- Cheropkina, Hanna,Catucci, Gianluca,Marucco, Arianna,Fenoglio, Ivana,Gilardi, Gianfranco,Sadeghi, Sheila J.
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- New insights into the photoreactivity of the organophosphorus pesticide fenthion: A σ aryl cation as a key intermediate in the photodecomposition
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The primary photodegradation processes of fenthion (FN), one of the most photosensitive pesticides used in agriculture, have been investigated by combining laser flash photolysis and steady-state measurements. The triplet state of FN is produced quite efficiently (Φisc~0.3). However, this excited state does not seem to trigger the primary photodecomposition pathways of the pesticide. It is demonstrated that FN undergoes photoheterolysis via the excited singlet state and gives the corresponding singlet σ aryl cation . Chemical evidence for the generation of this transient species is given by trapping with typical σ nucleophiles such as chloride and methanol. This photodegradation mechanism is, in part, quite different with respect to what is known to date and may account for the formation of the O,O-dimethyl S-[3-methyl-4-(methylthio)phenyl] phosphorothioate discovered as a novel photodegradation product of FN.
- Torrisi, Stefano,Sortino, Salvatore
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p. 5943 - 5949
(2007/10/03)
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- The role of carbonate radical in limiting the persistence of sulfur-containing chemicals in sunlit natural waters
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Carbonate radical (·CO3/-) is a selective oxidant that may be important in limiting the persistence of a number of sulfur-containing compounds in sunlit natural waters. Thioanisole, dibenzothiophene (DBT), and fenthion were selected
- Huang, Jiping,Mabury, Scott A.
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p. 1775 - 1782
(2007/10/03)
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- Hydrolysis kinetics of fenthion and its metabolites in buffered aqueous media
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This study investigates the hydrolysis kinetics of fenthion and its five oxidation metabolites in pH 7 and pH 9 buffered aqueous media at 25, 50, and 65 °C. Five metabolites and three hydrolysis products were synthesized and purified. The reactant and the corresponding hydrolysis products were determined by HPLC. Rate constant and half-life studies revealed that fenthion and its metabolites were relatively stable in neutral media, and their stability decreased as pH increased. The half-lives at 25 °C ranged from 59.0 days for fenthion to 16.5 days for fenoxon sulfone at pH 7, and from 55.5 days for fenthion to 9.50 days for fenoxon sulfone at pH 9; half- lives were greatly reduced at elevated temperatures. The activation energy (E(a)) was found to range from 16.7 to 22.1 kcal/mol for the compounds investigated. The phenol hydrolysis product of fenthion and fenoxon, 3- methyl-4-methylthiophenol was not stable in pH 7 and pH 9 buffered solutions at 50 °C, whereas 3-methyl-4-methylsulfonylphenol and 3-methyl-4- methylsulfinylphenol were relatively stable under the same conditions. At pH 9, the primary hydrolysis mechanisms of fenthion and its oxidation metabolites were combination of hydroxide ion and neutral water molecule attacking on the P atom to form corresponding phenol derivatives. Under neutral conditions, the primary hydrolysis mechanisms of fenthion and its oxidation metabolites were assumed to be the combination of water molecule attacking on the P atom to form phenol derivatives and on the C atom to yield dealkylation products.
- Huang, Jiping,Mabury, Scott A.
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p. 2582 - 2588
(2007/10/03)
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- Pesticidal compositions in paste form
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Novel pasty compositions for the control of animal pests and fungal diseases on plants, which compositions comprise at least one pesticidally active or fungicidally active compound and at least one adjuvant, which is solid, liquid or pasty at room temperature and optionally, one or more excipients and water.
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