The significance of xenobiotic-lipid conjugation.
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Animals↗
Biomedical subjects
D H Hutson
Publications and source records attributed to D H Hutson.
The fate of 4-cyano-N,N-dimethylaniline in mice: the occurrence of a novel metabolite during N-demethylation of an aromatic amine.
4-Cyano-N,N-dimethylaniline (CDA), when administered as a single oral dose to mice (18.5 mg/kg), was rapidly absorbed and eliminated. The major route of elimination was the urine (78% dose in 24h). The residues in the tissues 48 h after dosing, as microgram equiv. of CDA/g, were: liver, 0.19; kidney, 0.10; testes, 0.01; fat, 0.10; blood, 0.02. The major metabolite was 2-amino-5-cyanophenyl sulphate, with the N-methyl analogue as a minor metabolite. A novel metabolite, N-acetyl-S-(4-cyanoanilinomethyl)cysteine, was also a significant urinary metabolite, indicating that an electrophilic intermediate is generated during the N-demethylation of CDA. The implications are that N-demethylation may have important toxicological consequences.
Acetylcysteine↗
The metabolism of n-butyl glycidyl ether in the rat and rabbit.
[1-14C]Butyl glycidyl ether administered orally to male rats and rabbits (20 mg/kg) is rapidly absorbed and metabolized. Most of the administered compound, 87% (rat) and 78% (rabbit), is eliminated in the 0-24 urine. Major metabolites in the rat include 3-butoxy-2-hydroxypropionic acid (9%), 3-butoxy-2-acetylaminopropionic acid (23%) and butoxyacetic acid (10%). 3-Butoxy-2-hydroxypropionic acid (35%) and butoxyacetic acid (5%) are also major metabolites in the rabbit. Biotransformations of the glycidyl ether and their likely biochemical mechanisms are discussed.
Animals↗
The protective action of glutathione on the microbial mutagenicity of the Z- and E-isomers of 1,3-dichloropropene.
The Z(cis)- and E(trans)-isomers of 1,3-dichloropropene (DCP), in confirmation of previous reports, caused dose-dependent increases in the numbers of reverse mutations in Salmonella typhimurium TA100 in the presence and absence of a 9000 X g supernatant fraction (S9) from the livers of Aroclor-treated rats. The relevance of these findings to mammals is uncertain, not least because of major differences in the metabolism of the DCPs in the microbial assay systems and in vivo. For example, (Z)-DCP is efficiently detoxified in mammals by the operation of a glutathione (GSH)-dependent S-alkyl transferase. It is possible that such detoxification could proceed only very slowly in the microbial assays because the concentrations of GSH could be severely rate-limiting even in those assays fortified by the addition of S9. The results obtained in the current study demonstrate a dramatic reduction in the microbial mutagenicity of both (Z)- and (E)-DCP when the concentration of GSH in the microbial assays was adjusted to a normal physiological concentration (5 mM). However, this protective action of GSH was at least as effective in the absence of S9 as in its presence, suggesting that it was not mediated by mammalian GSH transferase. There appears to be little or no GSH alkyl or aryl transferase in the cytosol of S. typhimurium TA100, but intracellular GSH is present at a concentration similar to that found in mammalian cells. Since the uncatalysed reaction between the DCPs and glutathione is relatively slow, the effect is not due simply to their destruction by GSH. It is possible that a physiological concentration of extracellular GSH maintains the intracellular GSH in a reduced form in which its nucleophilic thiol group competes effectively with the nucleophilic centres in the bacterial DNA for the haloalkenes. The current results highlight the efficiency of GSH-linked systems in affording protection against the genotoxic action of the DCPs. It may be presumed that their operation would exert a major limiting effect on the genotoxicity of (Z)- and (E)-DCP in mammals.
Allyl Compounds↗
The metabolic fate of the herbicide nitralin in the rat.
14C-Nitralin (4-methylsulphonyl-2,6-dinitro-N,N-dipropyl-[14C]aniline) was dosed orally to rats (50 mg/kg). The radioactivity was quantitatively recovered (99.8%) between 0 and 72 h after dosing. Most of this was distributed equally between the urine and the faeces; about 1.5% was found in the carcass, skin and intestines. Structural analysis of the urinary metabolites showed that the metabolism proceeded via a complex multistep series of biotransformations involving nitro-group reduction, side-chain oxidation and removal and the subsequent formation of a variety of heterocyclic ring structures. A major metabolite was 7-amino-2-ethyl-5-methylsulphonyl-1-propylbenzimidazole; however, this accounted for only three-four per cent of the ingested radioactivity and was one of about five metabolites produced in this yield. Seven other metabolites were identified, none of which was derived from single-step biotransformation of nitralin. The latter, simpler, metabolites were detected on the incubation of nitralin with rat-liver enzymes of the type used in microbial mutagenicity testing. Two pathways (nitro-reduction and N-dealkylation) were observed under aerobic conditions but the former greatly predominated under anaerobic conditions.
Aniline Compounds↗
The fate of 4-cyano-N,N-dimethylaniline in rats; a novel involvement of glutathione in the metabolism of anilines.
4-Cyano-N,N-dimethylaniline (CDA), when administered to rats as a single oral dose (18.5 mg/kg), was rapidly absorbed and eliminated as a mixture of metabolites in the urine (86% dose after 24 h). Residues in tissues after 48 h, expressed as microgram equiv. of CDA, were: liver, 0.35; kidney, 0.28; testes, 0.08; fat, 0.06; bone marrow, 0.15 and blood, 0.32. Absorption, metabolism and elimination following four consecutive daily doses of CDA (65 mg/kg) were similar to those at the lower dose. The major metabolite was 2-amino-5-cyanophenyl sulphate with its mono- and di-N-methyl analogues as minor metabolites. 4-Cyanoaniline, its N-acetyl derivative and an unstable derivative were also found as metabolites. Three sulphur-containing metabolites with methylsulphinyl-, methylsulphonyl-, and N-acetylcysteinyl-groups attached to the C2 atom of an N-acetyl group were identified, the latter accounting for 10.3% and 4.1% of the low and high doses, respectively. The sulphur-containing metabolites indicate the involvement of glutathione in metabolism at the N-acetyl group. This implies the generation of an electrophilic intermediate, possibly the sulphate conjugate of an N-glycolylaniline, in the metabolism of CDA.
Aniline Compounds↗
The metabolism of ethylbenzene hydroperoxide in the rat.
Ethyl[14C]benzene hydroperoxide administered orally to female rats (30 mg/kg) is rapidly absorbed and metabolized. Most of the administered compound (81%) is eliminated in the 0-24 h urine. Major metabolites include mandelic acid (23%), hippuric acid (34%) and 1-phenylethyl glucuronide (4%). Ethyl[14C]benzene is metabolized via 1-phenylethanol to the same mixture of metabolites as obtained with the hydroperoxide. Biotransformations of the hydroperoxide and their likely biochemical mechanisms are discussed.
Animals↗
Microbial mutation studies with tetrachlorvinphos (Gardona)).
The mutagenic activity of tetrachlorvinphos was investigated in agar-layer cultures of Escherichia coli WP2 and WP2 uvrA, Salmonella typhimurium TA1535, TA1538, TA98 and TA100. Assays were carried out both in the presence and in the absence of S9 fractions of liver homogenates from rats and mice, both from untreated animals, and from animals pre-treated with Aroclor 1254. The induction of mitotic gene conversion by tetrachlorvinphos was studied in stationary phase cultures of the yeast Saccharomyces cerevisiae D4. No mutagenic effects, as determined by reverse gene mutation, were detected in vitro in the bacterial/mammalian microsome assay when a range of bacterial tester strains were exposed to tetrachlorvinphos at amounts up to 2000 micrograms per plate, either in the absence or in the presence of S9 fractions from non-induced or Aroclor-induced mouse or rat livers. Tetrachlorvinphos did not increase the mitotic gene conversion frequency in stationary phase cultures of the yeast, Saccharomyces cerevisiae D4.
Animals↗
Metabolism of the epoxy resin component 2,2-bis[4](2,3]epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part I. A comparison of the fate of a single dermal application and of a single oral dose of 14C-DGEBPA.
1. 14C-DGEBPA dermally applied to mice was only slowly eliminated in the feces (20% dose) and urine (3%), as a mixture of metabolites, over three days. Most of the applied radioactivity (66% dose) was extracted from the application area and its covering foil. 2. When 14C-DGEBPA was given orally to mice it was rapidly excreted; 80% of the administered 14C was eliminated in the feces and 11% in the urine 0-3 days after a single oral dose. 3. The urinary faecal metabolite profiles derived from dermal application and oral dosing were essentially similar.
Administration, Oral↗
Metabolism of the epoxy resin component 2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part II. Identification of metabolites in urine and faeces following a single oral dose of 14C-DGEBPA.
1. The major metabolic transformation of orally ingested 14C-DGEBPA is by hydrolytic ring-opening of the two epoxide rings to form diols. This metabolite (the bis-diol of DGEBPA) is excreted in both free and conjugated forms and is further metabolized to various carboxylic acids, including two containing a methylsulphonyl moiety. 2. The product of oxidative dealkylation either of DGEBPA (with concomitant formation of glycidaldehyde) or of the bis-diol of DGEBPA (with concomitant formation of glyceraldehyde) is excreted in both free and conjugated forms in amounts representing 5% of the dose. 3. The high activity of epoxide hydratase towards DGEBPA suggests that glyceraldehyde and not glycidaldehyde is formed in vivo. 4. Hepatic epoxide hydratase activity towards DGEBPA measured in vitro decreased in the order rabbit greater than mouse greater than rat. 5. Two discrete epoxide hydratases are present in large amounts in the mouse. One is membrane-bound in the liver microsomal fraction and the other is a "soluble' enzyme located in the liver cytosol. This cytosolic enzyme was present in only very small amounts in the rat.
Administration, Oral↗
Species variations in the renal and hepatic conjugation of 3-phenoxybenzoic acid with glycine.
1. 3-Phenoxy[14C]benzoyl-CoA has been chemically synthesized, purified and characterized by field-desorption mass spectrometry. Biological activity of the purified thioester was greater than 92%. 2. The two enzymic steps involved in the conjugation of 3-phenoxybenzoic acid (3PBA) with glycine have been investigated in hepatic and renal tissues from various mammalian species. 3. A 10- to 300-fold excess of acyl-CoA: glycine N-acyltransferase activity as compared with acyl-CoA synthetase activity was found in most tissue preparations, while the rate of the activating step matched that of the overall process. This suggests that formation of the acyl-CoA thioester (3PBA-CoA) is the rate-limiting step in the conjugation of 3PBA with glycine. 4. In most of the species tested, renal activities were higher than those of corresponding liver preparations. 5. The gerbil and ferret, which excrete 3-phenoxybenzoylglycine as the principal urinary metabolite of 3PBA, gave the highest 3PBA-CoA synthetase and glycine N-acyltransferase activities in vitro. By contrast, the hamster, which excretes only small amounts of the glycine conjugate of 3PBA, had the lowest enzymic activities in vitro. 6. In the mouse and rat there were differences between the patterns of metabolism found in vivo and in vitro, and possible reasons for this are discussed.
Acetate-CoA Ligase↗
The effect of hepatic microsomal monooxygenase induction on the metabolism and toxicity of the organophosphorus insecticide chlorfenvinphos.
The induction of rat liver microsomal monooxygenase by pretreatment of rats with dieldrin affords a 10-fold protection against the acute toxic effects of the organophosphorus insecticide, chlorfenvinphos. Metabolism studies were carried out to confirm that the protection was due to an enhanced rate of detoxification (via oxidative deethylation). At low doses of chlorfenvinphos (2.5 mg . kg-1), dieldrin pretreatment caused minimal changes in the metabolic profiles. However, at a higher dose (13.2 mg . kg-1), giving clinical signs of intoxication in the control animals, the dieldrin pretreated rats produced 5 times more deethylchlorofenvinphos than did the control animals. The results support the conclusion that the effect of enzyme induction on the metabolism of substrates of that enzyme are dose-dependent. Alterations in metabolism, therefore, are not an automatic consequence of enzyme induction.
Animals↗
Comparative metabolism of phenobarbitone in the rat (CFE) and mouse (CF1).
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Animals↗
Analysis of human urine for a metabolite of endrin by chemical oxidation and gas-liquid chromatography as an indicator of exposure to endrin.
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Chromatography, Gas↗
The metabolism of 3-chloro-4-fluoro-aniline in dog and rat.
1. 3-Chloro-4-fluorol[14C]aniline, orally administered to a female dog (0.135 mg/kg), was eliminated in the urine as 2-amino-4-chloro-5-fluorophenyl sulphate (83% in 48 h). 2. When 3-chloro-4-fluoro[14C]aniline was administered orally to male rats (ca 2.3 mg/kg), the 0-24 h urine contained 2-amino-4-chloro-5-fluorophenyl sulphate (52% of the aniline dosed), N-(5-chloro-4-fluoro-2-hydroxyphenyl)acetamide (13%) and an unidentified metabolite (16%). 3. 2-Amino-4-chloro-5-fluorophenyl sulphate was identified after extraction as salts by proton and fluorine-19 magnetic resonance spectroscopy. N-(5-Chloro-4-fluoro-2-hydroxyphenyl)acetamide was identified by mass spectrometry and proton magnetic resonance spectroscopy.
Aniline Compounds↗
The metabolic fate of a herbicidal methylmercapto-s-triazine (cyanatryn) in the rat.
1. A major route of metabolism of the methylmercaptotriazine herbicide cyanatryn involves S-oxygenation. 2. The S-oxide reacts spontaneously with glutathione affording a conjugate, which is eliminated in the bile, and a mercapturic acid which is eliminated in the urine. 3. A small proportion of the administered dose was covalently bound to a component of the blood, probably haemoglobin. This was shown to be dependent on the formation of the S-oxide and on the species of animal studied. 4. No reactivity of the S-oxide towards DNA in vivo or in vitro could be demonstrated.
Acetylcysteine↗
S-oxygenation of an alkylmercaptotriazine herbicide by rat, rabbit and human liver enzymes.
1. The oxidation of the herbicide cyanatryn to cyanatryn S-oxide and de-ethylcyanatryn was used to study S-oxidation and N-de-ethylation in liver microsomes from three species. 2. Both reactions were dependent upon NADPH and were inhibited by methyrapone and CO. However, the enzyme catalysing N-de-ethylation exhibited different species/sex specificity from the S-oxygenase. 3. Rat liver flavoprotein S-oxygenase had no action on cyanatryn, suggesting, with the other data, that the S-oxygenation was catalysed by cytochrome P-450. 4. S-Oxygenation proceeded rapidly in human liver microsomes and the rats was linear for 60 min at 37 degrees C.
Animals↗
Xenobiotic triglyceride formation.
1. When 3-phenoxy[14C]benzoic acid was dosed orally (0.76 mg/kg) to rats, 1--3% of the administered radioactivity was found in the skin four days after dosing. Approximately 90% of this residue was unchanged 3-phenoxybenzoate, 10% was a neutral compound. 2. The residue in the skins of rats dosed with 193 mg of 3-phenoxybenzoic acid over 7 days (c. 100 mg/kg per day) contained 40% 3-phenoxybenzoate and 60% neutral metabolites. 3. The components were separated and purified by gel permeation, absorption and t.l.c. and analysed by mass spectrometry. 4. 2- and 3-(3-Phenoxybenzoyl)dipalmitins were major components of the neutral metabolite.
Animals↗