PubMed Health⌕ Search

Biomedical subjects

D H Hutson

Publications and source records attributed to D H Hutson.

At least 19 recordsLinked to original sources
PubMed1998

The metabolism of 3-phenoxybenzoic acid-containing xenobiotic triacylglycerols in vitro by pancreatic, hormone-sensitive and lipoprotein lipases.

Two model substrates, rac-1-(3-phenoxy-[ring-14C]benzoyl)-2,3-dipalmitoyl glycerol (1(3PBA)DPG) and sn-2-(3-phenoxy-[ring-14C]benzoyl)-1,3-dipalmitoyl glycerol (2(3PBA)DPG), were compared with tri[1-14C]palmitoylglycerol or tri[9,10(n)-3H]oleoylglycerol as substrates for pancreatic lipase, lipoprotein lipase, and hormone-sensitive lipase. The loss of 3PBA from the sn-2 position was always low because of the positional specificity of the lipases. The loss of 3PBA from the rac-1 position was similarly low with hormone-sensitive lipase (about 7% of the loss of oleate), but higher with pancreatic lipase (about 35% that of oleate) and lipoprotein lipase (about 23% that of oleate). With one exception, more than 50% and up to 80% of the 14C-3PBA was still in the form of a diacylglycerol after incubation with a lipase, whereas free acid or monoacylglycerol forms would have been expected. Lipoprotein lipase acting on 1-(14C-3PBA)DPG produced nearly 70% of its product as nonesterified 3PBA and only 25% as the diacylglycerol. The results suggest that 3PBA-containing xenobiotic triacylglycerols, and the 3PBA-glycerol ester bond in particular, are poorer substrates for lipases than are their natural counterparts, with the result that high proportions of partially digested xenobiotic acylglycerols are produced. The three lipases performed differently with the xenobiotic substrates; this could have consequences for the relative rates of storage and clearance of the xenobiotic triacylglycerols from the body.

Animals↗
PubMed1998

The metabolism of the xenobiotic triacylglycerols, rac-1- and sn-2- (3-phenoxybenzoyl)-dipalmitoylglycerol, following intravenous administration to the rat.

The metabolism of 3-phenoxybenzoic acid (3PBA) in the form of triacylglycerol conjugates was compared with that of non-esterified 3PBA. Three radiolabeled triacylglycerols (rac-1-(3-phenoxy-[ring-14C]-benzoyl)-2,3-dipalmitoylglycerol (1(3PBA)DPG), sn-2-(3-phenoxy-[ring-14C]benzoyl)-1,3-dipalmitoylglycerol (2(3PBA)DPG) and the "natural" tri-[1-14C]oleoylglycerol) were incorporated into rat VLDL. Nonesterified 3PBA was prepared in rat serum albumin solution. Each preparation was administered i.v. to rats and serial blood samples were taken during the subsequent 6 hr. Urine and faeces were collected and tissue residues determined at 6 hr and 48 hr after administration. Biphasic elimination of 3PBA was observed with half-lives of 18 min and 2 hr. The triacylglycerols showed a rapid first phase and a longer second phase half-life: trioleoylglycerol 26 hr, 1(3PBA)DPG 7.6 hr and 2(3PBA)DPG 17.3 hr. The majority (63-76%) of 3PBA (whether esterified or not) was eliminated within 24 hr in urine, which contained similar profiles of metabolites. The triacylglycerols gave rise to higher tissue residues than did non-esterified 3PBA, particularly in adipose tissue which alone was not significantly depleted of radioactivity between 6 and 48 hr. The results accord with the rapid association of the VLDL-(3PBA)DPG complexes with lipoprotein lipase of the capillary epithelium, followed by hydrolysis to 3PBA, metabolism and elimination but with a proportion being redistributed into adipose tissue, re-esterified and then eliminated relatively slowly.

Animals↗
PubMed1991

Xenobiotic triacylglycerol formation in isolated hepatocytes.

The formation of neutral lipophilic metabolites from five xenobiotic carboxylic acids was studied in isolated rat hepatocytes. Oleic acid was used as a positive control. Rates of formation of lipids lay in the order: oleic acid greater than phytanic acid greater than ibuprofen greater than 3-phenoxybenzoic acid greater than indomethacin and 3-phenylbutanoic acid (rates were undetectable with the last two substrates). The process was saturable with the maximum rates at about 0.5 mM substrate concentration. Supplementation of the hepatocyte system with glycerol enhanced the yields of lipid products. The hepatocytes also effectively modelled the in vivo metabolism of ibuprofen, 3-phenoxybenzoic acid and 3-phenylbutanoic acid with oxidations and classical conjugation reactions predominating over xenobiotic lipid formation.

Animals↗
PubMed1991

Metabolism in the rat of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine.

1. The metabolism of a model xenobiotic plant metabolite S-benzyl-N-malonyl-L-cysteine (BMC) administered to rat at 10 mg/kg has been studied using a combination of radio-t.l.c. and h.p.l.c. 2. The major route of excretion for the administered 14C was via the urine (79% in 3 days). 3. The major metabolite was hippuric acid. The extent of biotransformation of BMC indicated the lability of the N-malonyl bond whose hydrolytic removal initiated a metabolic sequence which involved the action of C-S lyase to produce benzyl thiol. 4. A comparison of the findings from this study with those from experiments with N-acetyl-S-benzyl-L-cysteine and S-benzyl-L-cysteine is made to support the metabolic pathway proposed.

Animals↗
PubMed1990

The incorporation of 3-phenoxybenzoic acid and other xenobiotic acids into xenobiotic lipids by enzymes of the monoacylglycerol pathway in microsomes from adult and neonatal tissues.

The incorporation of 3-phenoxybenzoic acid (3PBA) into xenobiotic lipids by enzymes of the monoacylglycerol (MG) pathway was measured using microsomes prepared from rat liver as an enzyme source. The mean activities of the three enzymes involved were: acyl-CoA synthetase, 1.1 nmol/min/mg protein; MG acyltransferase, 75 pmol/min/mg protein; and diacylglycerol acyltransferase, 11.4 pmol/min/mg protein. MG and DG acyltransferase also showed activity with benzoyl-CoA or 1-naphthylacetyl-CoA as acyl donor but none with clofibryl-CoA or 2,4-dichlorophenoxyacetyl-CoA. MG acyltransferase activity, using 3PBA-CoA, was higher in microsomes from rat intestinal mucosa and pig liver, and lower in rat adipose tissue, rat liver and mouse liver. This ranking of activities corresponds to published activities using natural substrates. There was a large increase in MG acyltransferase, using either 3PBA-CoA or palmitoyl-CoA as substrate, in microsomes from the livers of rats 16-18 days old. Lysophosphatidic acid (lyso-PA) and lysophosphatidylethanolamine (lyso-PE), but not other phospholipids or detergents, stimulated MG acyltransferase activity more than two-fold. Lyso-PA (5 microM) increased the Vmax but had little effect on the Km for 2-hexadecylglycerol, whereas 100 microM lyso-PE decreased the Km and had a smaller effect on the Vmax. These results illustrate that the incorporation of xenobiotic acids into diacyl- and triacylglycerol by enzymes of the MG pathway may be a more general phenomenon than was previously suspected and that it may be subject to a variety of developmental and physiological controls.

Acyltransferases↗
PubMed1989

Activation of protein kinase C by an aromatic xenobiotic diacylglycerol analogue.

A number of xenobiotic carboxylic acids, including 3-phenoxybenzoic acid (3PBA), have been shown to form 'hybrid' di- and tri-acylglycerols both in vivo and in vitro. Experiments were carried out to test the hypothesis that naturally occurring xenobiotic diacylglycerols may stimulate protein kinase C. The activity of protein kinase C was measured in the presence of different diacylglycerols. 1-Acyl-2-(3PBA)-sn-glycerol but not 1,2-di-3PBA-sn-glycerol stimulated protein kinase C, but less effectively than either dioleoylglycerol or phorbol 12-myristate 13-acetate. The xenobiotic diacylglycerols were also more resistant to lipolysis. The possibility exists therefore that some xenobiotic diacylglycerols may behave, like phorbol diesters, as tumour promoters.

Animals↗
PubMed1988

The genetic toxicology of some hydrocarbon and oxygenated solvents.

Two hydrocarbon solvents (heptane and Special Boiling Point Spirit 100/140) and eight oxygenated solvents [methyl ethyl ketone, methyl isobutyl ketone, diacetone alcohol, di-isobutyl ketone, isopropyl ether, hexylene glycol, secondary butyl alcohol and ME 6K (pentoxone)] have been tested for genotoxic activity. The solvents were tested in bacterial mutation assays, a yeast assay for mitotic gene conversion and in cultured mammalian cells (either rat liver or Chinese hamster ovary) for structural chromosome damage. All of the solvents gave a negative response in the bacterial mutation assays and the yeast mitotic gene conversion assay. In the rat liver chromosome assay, diacetone alcohol evoked a weak positive response, the remaining solvents gave a negative response.

Alcohols↗
PubMed1988

Elimination and accumulation of the rodenticide flocoumafen in rats following repeated oral administration.

1. Following multiple oral administration of 14C-flocoumafen to rats at 0.02 and 0.1 mg/kg per week, appreciable cellular accumulation was seen in the liver. 2. Residues in the liver increased with dose throughout the duration of the experiment (14 weeks) at the low dose, but reached a plateau after 4 weeks at the high dose. The major component was unchanged flocoumafen together with a minor polar metabolite seen also in faeces. 3. The data suggest the presence in rat liver of a saturable high-affinity binding site for flocoumafen and a second binding site of lower affinity. 4. Lethal anticoagulant action occurs only when the binding sites have become saturated. 5. A range of haematological and clinical chemistry measurements failed to predict the onset of anticoagulant toxicity seen in the high dose treatment group. 6. Flocoumafen was not extensively metabolised; at the low dose, approximately 30% of the cumulative administered dose was eliminated in the faeces within 3 days of each dosing, mainly as unchanged rodenticide. At the high dose, this value ranged from 18% after the first dose to 59% after the tenth dose. 7. Two more polar metabolites and a lipophilic compound were minor products in faeces. Amounts of the polar products increased with cumulative dosage received. The urinary route of elimination was a very minor one (less than 1.6%) at both doses.

4-Hydroxycoumarins↗
PubMed1988

The fate of 4-cyanoacetanilide in rats and mice; mechanism of formation of a novel electrophilic metabolite.

1. The metabolic fate of 4-cyanoacetanilide (CAA), labelled with 14C and 13C in the N-acetyl group, was studied in rats (oral dose, 22.5 mg/kg) and mice (oral dose 21.7 mg/kg). 2. The metabolic profile in the urine of rats was compared with that obtained previously with 4-cyano-N,N-dimethylaniline (CDA) and confirms the intermediacy of CAA in the metabolism of CDA. 3. The precursor of a major metabolite of CDA and CAA (the mercapturic acid N-acetyl-S-[2-keto-2-(4-cyanoanilino)ethyl]cysteine, metabolite C) was identified in the urine of CAA-dosed rats as the O-sulphate conjugate of N-(4-cyanophenyl)glycolamide. 4. Pretreatment of rats with the sulphotransferase inhibitor pentachlorophenol reduced the yield of the mercapturic acid metabolite C, further indicating the intermediacy of a sulphate conjugate. 5. Metabolite C was not formed from CAA by mice; thus, this species difference, also observed with CDA, occurs at the level side-chain (acetyl) hydroxylation as well as at N-acetylation of 4-cyanoaniline as previously proposed. 6. The significance of this pathway as a bioactivation reaction of CDA, CAA and other acetanilides is discussed.

Acetanilides↗
PubMed1987

Microbial mutagenicity studies with (Z)-1,3-dichloropropene.

This study has confirmed that the direct mutagenicity previously observed when S. typhimurium TA100 was treated with (Z)-1,3-dichloropropene (DCP) was in fact due to trace impurities. These impurities result from autoxidation of (Z)-1,3-DCP and have now been identified. Both (Z)- and (E)-2-chloro-3-(chloromethyl)oxiranes (DCP oxides) were identified as significant products during this autoxidation. The mutagenic impurities formed by autoxidation were completely removed by adsorption chromatography on silicic acid. (Z)-1,3-DCP purified in this way had no direct-acting mutagenicity towards S. typhimurium TA100. However, (Z)-1,3-DCP undergoes mono-oxygenase-catalysed conversion into bacterial mutagens in the presence of S9 fraction or washed microsomes from rat liver. The glutathione-linked conjugation systems of mammalian tissues provided efficient protection against this indirect mutagenic action. However, the low concentration of glutathione in standard bacterial mutagenicity assays limits the glutathione S-alkyl transferase-catalysed detoxification of (Z)-1,3-DCP and its primary bioactivation product(s). When the concentration of glutathione was adjusted to the normal physiological concentration, the mono-oxygenase-dependent mutagenic action of (Z)-1,3-DCP was virtually eliminated. These results therefore are consistent with the view that bacterial mutation assays are only qualitative indicators of potential mammalian genotoxicity.

Allyl Compounds↗
PubMed1987

The toxicity and metabolism of the pyrethroids cis- and trans-cypermethrin in rainbow trout, Salmo gairdneri.

1. The toxicity of cis- and trans-cypermethrin to rainbow trout was investigated and the concentrations of the two isomers in brain associated with toxic signs (excitability and loss of equilibrium) were determined. cis-Cypermethrin and trans-cypermethrin were equally toxic and showed similar brain levels associated with toxic signs (cis:0.25 micrograms/g, mean (range 0.07-0.53); trans:0.17 micrograms/g (0.07-0.31]. 2. Orally administered cypermethrin was less toxic than predicted, probably due to poor intestinal uptake. Toxicity was due to absorption via the gills of unchanged pyrethroid excreted from the intestine into the water. 3. The metabolism of the radiolabelled insecticides, [14C-cyclopropyl]- and [14C-benzyl]-cis- and trans-cypermethrin has been investigated in vivo and in vitro. 4. The principal route of elimination in vivo was the bile, with 20-28% dose excreted as biliary metabolites in 24 h. No difference in the rates of elimination of the cis and trans isomers was observed. 5. cis-Cypermethrin was metabolized primarily to the glucuronide of 4'-hydroxy-cypermethrin (80% total bile radioactivity), together with dichlorovinyldimethylcyclopropanecarboxylic acid and its glucuronide, 3-(4-hydroxyphenoxy)benzoic acid (4'-hydroxy-3BPA) and its ester and ether glucuronides, 3-phenoxybenzoyl glucuronide and 4'-hydroxy-3BPA sulphate were detected. trans-Cypermethrin was metabolized to the same products, but with only 36% as 4'-hydroxy-cypermethrin glucuronide.

Animals↗
PubMed1986

Comparative toxicity of cis-cypermethrin in rainbow trout, frog, mouse, and quail.

The synthetic alpha-cyano-phenoxybenzyl-containing pyrethroid insecticides act on the CNS of vertebrates and show a species-selective toxicity in the order fish greater than amphibians much greater than mammals greater than birds. Concentrations of [14C]cis-cypermethrin in the brains of representative members of each of these classes of chordates were measured at toxic signs (an onset of hyperactivity followed by seizures and loss of balance/equilibrium) as an indicator of target organ sensitivity. The concentration of cis-cypermethrin in brain, associated with toxic signs, in micrograms per gram (mean +/- SE) as determined by high-performance liquid chromatography was 0.08 +/- 0.03 (frog), 0.23 +/- 0.05 (trout), 1.71 +/- 0.33 (mouse), and 3.94 +/- 0.88 (quail). Trout brain was equally sensitive to the cis and trans isomers of cypermethrin. In both mouse and quail, some 90% of the radioactivity in the brain was parent pyrethroid. Trout and frog, however, afforded only 56 and 32%, respectively, of the brain 14C as cypermethrin, with the remaining radioactivity in both extractable and nonextractable metabolites, including 4'-hydroxy-cis-cypermethrin, which is potentially neuroactive. Following oral administration, cis-cypermethrin was readily absorbed and metabolized by quail. Intestinal uptake was far less rapid in trout and mouse, with unchanged cypermethrin dispersed in secreted bile, being readily eliminated from the intestines of fish. The uptake and metabolism of cis-cypermethrin and the brain sensitivities of these animals to the pyrethroid account for the observed differences in acute toxicity.

Animals↗
PubMed1986

A comparison of the metabolic fate of phenol, phenyl glucoside and phenyl 6-O-malonyl-glucoside in the rat.

The metabolic fates of 14C-phenol and its model plant conjugates 14C-phenyl glucoside and 14C-phenyl 6-O-malonyl-glucoside have been compared following equimolar oral dosing to rats (1.2 mg phenol/kg). Rapid excretion of radioactivity in the urine (at least 80% within 24 h) was observed with each compound. Phenol was eliminated as expected mainly as phenyl sulphate (68%) and partly as phenyl glucuronide (12%). The excretion profile for phenyl malonyl-glucoside was very similar to that of phenol, with the exception that small amounts of phenyl glucoside and phenyl malonyl-glucoside were excreted. In contrast, a major part of the dose of phenyl glucoside was eliminated unchanged. The value of metabolism studies in the assessment of the toxicology of xenobiotic metabolites derived from plants is discussed.

Animals↗
PubMed1986

Detoxification of the organophosphorus insecticide chlorfenvinphos by rat, rabbit and human liver enzymes.

A good inverse correlation between the acute oral toxicity of chlorfenvinphos and its rate of oxidative detoxification in the liver exists for rats, mice, rabbits and dogs. Measurements of the rates of oxidative metabolism (O-de-ethylation) by in vitro liver preparations from rat, rabbit and human have been compared. When the results are expressed in terms of cytochrome P450, as opposed to microsomal protein, detoxification by the human liver enzyme(s) is almost as effective as that by rabbit enzyme(s). The rabbit is relatively resistant to the acute toxic action of the insecticide.

Animals↗
PubMed1986

The metabolism of o-fluoroaniline by rats, rabbits and marmosets.

o-Fluoroaniline is rapidly metabolized and excreted in rats, rabbits and marmosets. Following a single oral dose of 14C-fluoroaniline of about 20 mg/kg, more than 80% of the dose is excreted in 0-24 h, the urine being the major route of excretion for all three species. For all three species, 4-amino-3-fluorophenyl is a major metabolite, conjugated at oxygen with either sulphate or glucuronic acid. 4-Acetylamino-3-fluorophenyl sulphate or glucuronide are also significant metabolites. An h.p.l.c. method with electrochemical detection was developed for monitoring exposure of plant workers to o-fluoroaniline, based on 4-amino-3-fluorophenyl sulphate.

Aniline Compounds↗