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Biomedical subjects

D H Hutson

Publications and source records attributed to D H Hutson.

At least 55 records · Page 3Linked to original sources
PubMed1980

The metabolism of 3-phenoxybenzoic acid and its glucoside conjugate in rats.

1. 3-Phenoxy[14C]benzoic acid administered orally to rats (0.76 to > 100 mg/kg) is extensively metabolized and rapidly eliminated mostly via the urine. 2. The major metabolic pathway involves 4'-hydroxylation followed by conjugation of the resulting phenol with sulphate. Only minor amounts of amino acid and glucuronic acid conjugation were observed. 3. 3-Phenoxy[14C]benzoyl glucoside, derived from the metabolism of the acid by corn leaves, was also rapidly absorbed by rats and eliminated as a mixture of metabolites very similar to that derived from 3-phenoxybenzoic acid. It was concluded that the glucoside conjugate was rapidly hydrolysed to the free acid in vivo.

Animals↗
PubMed1979

The chemical and biochemical reactivity of dichlorvos.

The chemical structure, reactivity and metabolic fate of the insecticide dichlorvos (2,2-dichlorovinyl dimethyl phosphate) are discussed in relation to the possible genotoxicity of this and other methyl phosphate triesters. Recent attempts to demonstrate the methylation of DNA following exposure of bacteria and animals to dichlorvos are reviewed. On the basis of comparative data relating mutagenesis to methylation reactions, it seems entirely appropriate to conclude that the mutagenicity of dichlorvos to bacteria is due solely to methylation of the bacterial DNA under the conditions of these tests. However, the methylation of mammalian DNA could not be demonstrated under realistic exposure conditions (when the alkylating mutagen methyl methanesulphonate afforded clearly measurable methylation). The failure to detect methylation by dichlorvos in vivo is attributed to the operation of highly efficient enzyme-catalysed biotransformations which rely largely on the phosphorylating reactivity of dichlorvos. The biotransformation pathways, characterised mostly in the rat, appear to be common also to pig, mouse, hamster, and man.

Animals↗
PubMed1978

Taurine conjugation in metabolism of 3-phenoxybenzoic acid and the pyrethroid insecticide cypermethrin in mouse.

1. A substantial proportion of the radioactivity of an oral dose (1-20 mg/kg) of 3-phenoxy [14C] benzoic acid and the pyrethroid insecticide trans- and cis-[aryl-14C] cypermethrin (an alpha-cyano-3-phenoxybenzyl ester) is eliminated rapidly in urine of mice. 2. The major urinary metabolite of these compounds in two strains of mice is N-(3-phenoxybenzoyl)taurine. 3. Neither 3-phenoxybenzoic acid nor cypermethrin gives a taurine conjugate in rats. 4. Benzoic acid gives no taurine conjugate in mice.

Animals↗
PubMed1978

An example of the oxidative de-esterification of an isopropyl ester. Its role in the metabolism of the herbicide flampropisopropyl.

1. Two mammalian metabolites of the herbicidal ester, flamprop-isopropyl (BARNON), have been characterized as products of omega-hydroxylation of the isopropoxycarbonyl grouping (-CO2 CHMe 2). 2. Hydroxylation at the methine group of this moiety, to afford an unstable lactol (-CO2C(OH)Me2) and thence the corresponding carboxylic acid also appears to occur. On the basis of experiments with rat liver microsomes, this pathway to the acid may be as important as the esterase-catalysed route. 3. Biomimetic oxidation studies with peroxytrifluoroacetic acid of a simple model of the herbicide (isopropyl acetate) have provided confirmation of the feasibility of the novel biotransformation.

Anilides↗
PubMed1977

Some observations on the chemical and stereochemical specificity of the de-alkylation of organophosphorus esters by a hepatic glutathione transferase.

Hepatic glutathione (GSH) S-methyl transferase from rabbit, pig and dog demethylates dimethyl phosphate triesters. No stereospecificity towards racemic ethyl methyl 2-chloro-1-(2,4-dichlorophenyl)vinyl phosphate could be demonstrated but the enzyme exhibited some selectivity towards the (+) and (-) forms of O-methyl S-methyl 1-naphthyl phosphorothiolate. Pig liver enzyme, purified 30-fold, demethylated th prochiral substrate dimethyl 1-naphthyl phosphorothionate with 90% stero-selectivity.

Animals↗
PubMed1977

The fate of the herbicide flamprop-isopropyl (barnon) in rats and dogs.

1. [14C]Flamprop-isoppropyl (BARNON) administered orally to rats and dogs is excreted mostly via the faeces (90-5% and 76-3% in male and female rats respectively and 53% in dogs). Elimination was rapid from both species, and greater than 96% of the dose of 14C was excreted by rats 0-48 h after dosing. Distribution of 14C between urine and faeces was different in male and female rats, but the same for dogs of either sex. 2. The predominant metabolic pathway in both species was loss of the isopropyl group; the resulting carboxylic acid was excreted free and as the ester glucuronide. 3. Aromatic hydroxylation occurred at the para- and meta-positions of the N-benzoyl ring; the presence of a 3,4-dihydroxybenzoyl metabolite (but no dihydrodiol) suggests that arene oxide formation is involved. However, direct hydroxylation at position 3 cannot be precluded. Aromatic hydroxylation occurred with the following facility (0-48 h); male rat, 18%; female rat, 13%; dog (either sex), 2%. 4. Hydroxylation occurred readily in the isopropyl side chain yielding mostly a propan-1,2-diol ester in the dog. In the rat, this metabolite was mostly oxidized to yield a 2-lactyl ester.

Administration, Oral↗
PubMed1976

Metabolic demethylation of the insecticide dimethylvinphos in rats, in dogs, and in vitro.

1. The alkenyl phosphate insecticide, dimethylvinphos, is rapidly metabolized and eliminated by rats and dogs. 2. Metabolism proceeds via demethylation followed by the hydrolysis of desmethyl dimethylvinphos to 2,4-dichlorophenacyl chloride which is further metabolized mainly to 2,4-dichloromandelic acid, 1-(2,4-dichlorophenyl)ethanol (glucuronide) and 2,4-dichlorphenylethanediol (glucuronide). 3. The dechlorination of 2,4-dichlorophenacyl chloride to 2,4-dichloroacetophenone proceeds via the spontaneous formation of S-(2,4-dichlorophenacyl) glutathione which is converted to the ketone by an enzyme-catalysed glutathione-dependent reaction. 4. Demethylation of dimethylvinphos occurs in liver fractions via the action of two enzymes: glutathione S-methyl transferase in the cytosol, and microsomal mono-oxygenase. The relatively high activities of both enzymes in dog liver (compared with rat liver) partly account for the observed differences in metabolism and toxicity of dimethylvinphos in the two species. 5. The glutathione transferase is enhanced twofold by pre-treatment of rats with 0-1% phenobarbital in their drinking water. This treatment also induces the microsomal demethylation 45-fold and results in a greater than 13-fold protective effect against the acute toxic effects of dimethylvinphos.

Animals↗
PubMed1975

The metabolic fate of endrin in the rabbit.

1. [14C]Endrin, administered orally to rabbits, is excreted in the faeces as unchanged endrin (50% of that administered) and in the urine as a mixture of polar metabolites. 2. The major biotransformation is hydroxylation at the methylene bridge (C-12) to yield anti-12-hydroxyendrin. syn-Hydroxylation at C-12 also occurs. 3. The hydroxylated metabolites are excreted mainly as their sulphate conjugates. 4. Glucuronide conjugates are also excreted. anti-12-Hydroxyendrin is rapidly conjugated in vitro on incubation with rabbit liver microsomal glucuronyl transferase and UDPGA. 5. Comparative aspects of the metabolism of endrin in rats and rabbits are discussed.

Administration, Oral↗
PubMed1975

Detoxication and bioactivation of endrin in the rat.

1. Rats exhibit a sex difference in the rate of metabolism of endrin. 2. The major metabolite in both sexes is anti-12-hydroxyendrin which is excreted via the bile as the glucuronide. Male rats produce the metabolite at a higher rate than do females. 3. trans-4,5-Dihydroisodrin-4,5-diol is a minor metabolite. A mechanism for its formation is discussed. 4. There is a sex difference in the production and excretion of 12-ketoendrin which is observed as a urinary metabolite in male rat; the major urinary metabolite in female rats is anti-12-hydroxyendrin O-sulphate. 5. syn-12-Hydroxyendrin was not detected but may be an intermediate in the formation of 12-ketoendrin. 6. The formation of 12-ketoendrin is related to the acute toxicity of endrin.

Adipose Tissue↗
PubMed1972

The oxidative dealkylation of insecticidal phosphoric acid triesters by mammalian liver enzymes.

1. The dealkylation of the insecticidal phosphoric acid triester, 2-chloro-1-(2,4-dichlorophenyl)vinyl diethyl phosphate, proceeds in mammalian liver slices via an oxidative mechanism and not by hydrolysis. 2. The enzyme that catalyses the reaction is located in the microsomal fraction of liver homogenate and is dependent for activity on molecular oxygen and NADPH. 3. There are large species differences between rat, mouse, rabbit and dog in the activity of the enzymes, the relative rates of dealkylation being 1, 8, 24 and 88 respectively in liver slices. 4. Dimethyl and di-isopropyl phosphate triesters are also dealkylated by rabbit liver microsomal preparations. 5. The mechanism of dealkylation involves hydroxylation at the alpha-carbon atom of an alkyl group, which is removed as the corresponding aldehyde, and is thus analogous to that of similar reactions catalysed by the microsomal mixed-function oxidases. 6. The relevance of these findings in the toxicology of phosphoric acid triesters is discussed.

Alkylation↗
PubMed1972

Phosphoric acid triester glutathione alkyltransferase. A mechanism for the detoxification of dimethyl phosphate triesters.

1. 2-Chloro-1-(2,4,5-trichlorophenyl)vinyl dimethyl phosphate (tetrachlorvinphos) is demethylated by mammalian liver supernatant (100000g) protein in the presence of GSH. 2. GSH acts as an acceptor of the transferred methyl group to form S-methyl glutathione. 3. The enzyme that catalyses this reaction is present in the soluble fraction of liver from mouse, rat, rabbit and pig at similar activity. The enzyme was purified 45-fold from pig liver, dimethyl 1-naphthyl phosphate being used as assay substrate. 4. Methyl groups are readily removed from most of the substrates studied; ethyl groups are removed at one-fiftieth to one-hundredth of the rate for methyl groups. It is likely that the enzyme plays an important role in the detoxification of the phosphate triester pesticides containing CH(3)-O-P groups.

Animals↗