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E Hodgson

Publications and source records attributed to E Hodgson.

151 records · Page 9Linked to original sources
PubMedDate not supplied

Induction and inhibition of pesticide-metabolizing enzymes: roles in synergism of pesticides and pesticide action.

Synergism of the toxic action of pesticides is discussed with particular emphasis on the methylenedioxyphenyl (benzodioxole) (MDP) synergists and on how studies of these compounds may relate to the general significance of pesticide synergism. MDP compounds function as both inhibitors and inducers of cytochrome P450 isoforms, the two processes proceeding, in vivo, at different rates. Inhibition is mediated through the formation of metabolite inhibitory complexes, and induction involves both aryl hydrocarbon (Ah)-dependent and Ah-independent mechanisms. The significance of this biphasic effect on multienzyme xenobiotic metabolizing systems is illustrated by considerations of the insecticide phorate.

Cytochrome P-450 Enzyme System↗
PubMedDate not supplied

The role of the flavin-containing monooxygenase (EC 1.14.13.8) in the metabolism and mode of action of agricultural chemicals.

1. The flavin-containing monooxygenase (FMO) (EC 1.14.13.8) is a versatile enzyme that catalyses the monooxygenation of a large number of xenobiotic soft nucleophiles ranging from inorganic ions to organic compounds with nitrogen, sulphur, phosphorus or selenium heteroatoms. 2. The substrate specificity relative to agricultural chemicals is discussed and compared with that of the cytochrome P-450-dependent monooxygenase system. The relative activity of these two enzymes towards common substrates varies from substrate to substrate and from tissue to tissue as is shown in the case of the insecticide, phorate and the hepatotoxicant, thiobenzamide. 3. The products of FMO action may be chemically different (e.g. nicotine) to those from P-450, or the two enzymes may produce different isomers of the same product (e.g. phorate). 4. Recent studies have demonstrated that, in the rabbit, the FMOs from liver and lung are different gene products which differ not only in primary sequence but also in physical, catalytic and immunochemical properties. These studies are being extended to include other tissues such as skin and brain. 5. Immunocytochemical localization of FMO in lung and skin correlates well with measurements of the oxidation of methimazole, a specific FMO substrate.

Agrochemicals↗
PubMedDate not supplied

Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation.

Earlier studies demonstrated that the major metabolites of tamoxifen generated by mammalian liver microsomes are the corresponding N-oxide, N-desmethyl, and 4-hydroxy derivatives. This study examines the enzymatic activity catalyzing the formation of tamoxifen N-oxide by mammalian liver microsomes. Incubations of tamoxifen with liver microsomes from the various species, supplemented with NADPH, yielded the N-oxide, N-desmethyl, and 4-hydroxy derivatives. Inhibition of N-oxide accumulation by mild heat and low concentrations of methimazole in rat liver microsomes indicated that this reaction is catalyzed by the flavin-containing monooxygenase (FMO). Antibodies to NADPH-P-450 reductase inhibited N-demethylation and 4-hydroxylation, but not N-oxidation, supporting the aforementioned conclusion. Purified mouse liver microsomal FMO converted tamoxifen solely into the N-oxide, providing direct evidence for FMO involvement. Human liver microsomes formed the same tamoxifen metabolites, albeit at a much lower rate. Inhibitors of FMO diminished the accumulation of N-oxide by human liver microsomes, indicating involvement of FMO. Tamoxifen-N-oxide was found to be readily reduced to tamoxifen by rat or human liver microsomes, in the presence of NADPH; the extent of reduction was dramatically increased when incubations were supplemented with methimazole. The facile reduction of tamoxifen N-oxide back to tamoxifen suggests that the N-oxide may serve as a storage form for tamoxifen in vivo.

Animals↗