Metabolism of sinapic acid and related compounds in the rat.
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ABSTRACT:
SUBMITTER: Griffiths LA
PROVIDER: S-EPMC1184739 | biostudies-other | 1969 Jul
REPOSITORIES: biostudies-other
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Project description:1. The metabolism of (+/-)-norcamphor, (+)-camphor, (-)-camphor, (+)-epicamphor, (+/-)-camphorquinone, (+/-)-camphane-2,5-dione and camphane was investigated in rabbits. All the compounds except camphane-2,5-dione increased the content of glucuronide in the urine. 2. (+/-)-Norcamphor was reduced to endo-norborneol; (+)-camphor, contrary to expectation, was reduced to (+)-borneol, as well as being hydroxylated to (+)-5-endo-hydroxycamphor and (+)-3-endo-hydroxycamphor, 5-endo-hydroxycamphor being the predominant product. (+)-Epicamphor was reduced mainly to (+)-epiborneol; (+/-)-camphorquinone gave 3-endo-hydroxycamphor and 2-endo-hydroxyepicamphor, the former being the major metabolite. (+/-)-Camphane-2,5-dione was reduced to 5-endo-hydroxycamphor. Camphane was hydroxylated to borneol and epiborneol, the latter predominating. 3. An explanation of these findings is given in terms of steric hindrance and thermodynamic stability. 4. The possibility was investigated that NADH was involved in the reductions.
| S-EPMC1184604 | biostudies-other
Project description:1. A chromatographic investigation of the products of the metabolism of 3-methylcholanthrene by rat-liver homogenates showed the formation of compounds with the properties of 1- and 2-hydroxy-3-methylcholanthrene, cis- and trans-1,2-dihydroxy-3-methylcholanthrene and 11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene. A glutathione conjugate that is probably S-(11,12-dihydro-12-hydroxy-3-methyl-11-cholanthrenyl)glutathione was also detected. 3-Methylcholanthrene-1- and -2-one and -1,2-quinone were also present, but these products may have arisen by the chemical oxidation of the corresponding hydroxy compounds. 2. Other metabolic products were tentatively identified as 9- and 10-hydroxy-3-methylcholanthrene, 4,5-dihydro-4,5-dihydroxy-3-methylcholanthrene and 3-hydroxymethylcholanthrene. 3. 1- and 2-Hydroxy-3-methylcholanthrene were converted by homogenates into the related ketones and into products with the properties of cis- and trans-1,2-dihydroxy-3-methylcholanthrene: 3-methylcholanthren-1- and -2-one were converted into their related hydroxy compounds and into the isomeric 1,2-dihydroxy compounds. The isomeric 1,2-dihydroxy compounds were each partly converted into the other isomer by these homogenates. All the above substrates also yielded products that appeared to be derivatives of 3-hydroxymethylcholanthrene. 4. 3-Methylcholanthrylene was converted by rat-liver homogenates into products with the properties of trans-1,2-dihydroxy-3-methylcholanthrene, 2-hydroxy-3-methylcholanthrene and 3-methylcholanthren-2-one. A small amount of the cis-1,2-dihydroxy compound was also formed, together with a glutathione conjugate that is possibly S-(2-hydroxy-3-methyl-1-cholanthrenyl)glutathione or its positional isomer. 5. An unidentified product was detected in the metabolism of 3-methylcholanthrene, the monohydroxy compounds, the ketones and the dihydroxy compounds, the formation of which appeared to involve metabolism at the 1,2-bond. 6. 11,12-Epoxy-11,12-dihydro-3-methylcholanthrene was converted by rat-liver homogenates into products with the properties of 11-hydroxy-3-methylcholanthrene (or, less likely, the 12-isomer), 11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene and the glutathione conjugate described above. Products with the properties of these compounds were formed when the epoxide was allowed to react with glutathione in an aqueous medium. 7. Mouse-liver homogenate converted 3-methylcholanthrene into products with the chromatographic properties of 1- and 2-hydroxy-3-methylcholanthrene, cis- and trans-1,2-dihydroxy-3-methylcholanthrene, 11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene, 3-methylcholanthrene-1- and -2-one and -1,2-quinone and the unidentified hydroxy-3-methylcholanthrenes. 8. The syntheses of cis- and trans-1,2-dihydroxy-3-methylcholanthrene, 3-methylcholanthren-2-one, 2-hydroxy-3-methylcholanthrene, 3-methylcholanthrylene, 11,12-epoxy-11,12-dihydro-3-methylcholanthrene and trans-11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene are described.
| S-EPMC1264818 | biostudies-other
Project description:Methyleugenol, the methyl ether of eugenol, both of which are flavorant constituents of spices, has been listed by the National Toxicology Program's Report on Carcinogens as reasonably anticipated to be a human carcinogen. This finding is based on the observation of increased incidence of malignant tumors at multiple tissue sites in experimental animals of different species. By contrast, eugenol is not listed. In this study, we show that both methyleugenol and eugenol readily undergo peroxidative metabolism in vitro to form free radicals with large hyperfine interactions of the methylene allylic hydrogen atoms. These large hyperfine splittings indicate large electron densities adjacent to those hydrogen atoms. Methyleugenol undergoes autoxidation such that the commercial product contains 10-30 mg/L hydroperoxide and is capable of activating peroxidases without the presence of added hydrogen peroxide. Additionally, the hydroperoxide is not a good substrate for catalase, which demonstrates that these antioxidant defenses will not be effective in protecting against methyleugenol exposure.
| S-EPMC4002132 | biostudies-other
Project description:Cytosol preparations of rat liver and kidney were examined for their ability to transfer sulphate from adenosine 3'-phosphate 5'-sulphatophosphate to p-hydroxyphenylpyruvic acid. Little activity towards this substrate was observed, and the main product detected in the reaction mixtures was identified as p-hydroxybenzyl alcohol O-sulphate. This was not formed from p-hydroxybenzaldehyde, a spontaneous oxidation product of p-hydroxyphenylpyruvic acid, by sulphation followed by a rapid enzyme-catalysed reduction of the intermediate phydroxybenzaldehyde O-sulphate. This product was formed mainly by this sequence of reactions, but the reverse, reduction followed by sulphation, also appeared possible. p-Hydroxybenzyl alcohol itself was very readily sulphated by both preparations, and the liver also produced a sulpho-conjugate of homogentisic acid. These observations are important in calculating the turnover of L-tyrosine O-sulphate in the mammalian system, and establish that p-hydroxyphenylpyruvic acid O-sulphate is an end product of its metabolism, rather than an intermediate in its synthesis by reversed transamination.
| S-EPMC1165723 | biostudies-other
Project description:1. 7,12-Dimethylbenz[a]anthracene is converted by rat-liver homogenates into products with the properties of the 7- and 12-hydroxymethyl derivatives, the 7,12-dihydroxymethyl derivative, the related carboxylic acids and ring-hydroxylated products such as the 8,9-dihydro-8,9-dihydroxy derivative and phenols. Ring-hydroxylated products and products arising from the further oxidation of the hydroxymethyl groups were formed when the hydroxymethyl derivatives were themselves incubated with rat-liver homogenates. 2. Pretreatment of the animal with 3-methylcholanthrene or with Sudan III, which can protect rat adrenal glands from damage by 7,12-dimethylbenz[a]anthracene or by its 7-hydroxymethyl derivative, led to an increased rate of metabolism of 7,12-dimethylbenz[a]anthracene and its hydroxymethyl derivatives. The metabolic routes mainly affected were those involving the formation of ring-hydroxylated products. 3. Pretreatment with phenobarbitone led to a small increase in the rate of metabolism of the hydrocarbon and of its hydroxymethyl derivatives, but the increase appeared mainly to involve increased metabolism of the methyl and hydroxymethyl groups. 4. Pretreatment with metyrapone increased the rate of metabolism of the hydrocarbon mainly by increasing the amounts of products resulting from hydroxylation of the methyl groups: small increases in the amounts of ring-hydroxylated products were also produced. 8. Of a number of hydrocarbons and of derivatives of 3-methylcholanthrene tested as enzyme inducers, 3-methylcholanthrene itself was the most effective.
| S-EPMC1270599 | biostudies-other
Project description:Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I, and their glucuronide and sulfate conjugates that can be found in urine and feces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urine using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I, and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules, whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate, whereas the conjugated metabolites are almost exclusively secreted to the urine.
| S-EPMC3276251 | biostudies-literature
Project description:Dietary n-6 polyunsaturated fatty acid (PUFA) deprivation in rodents reduces brain arachidonic acid (20:4n-6) concentration and 20:4n-6-preferring cytosolic phospholipase A(2) (cPLA(2) -IVA) and cyclooxygenase (COX)-2 expression, while increasing brain docosahexaenoic acid (DHA, 22:6n-3) concentration and DHA-selective calcium-independent phospholipase A(2) (iPLA(2) )-VIA expression. We hypothesized that these changes are accompanied by up-regulated brain DHA metabolic rates. Using a fatty acid model, brain DHA concentrations and kinetics were measured in unanesthetized male rats fed, for 15 weeks post-weaning, an n-6 PUFA 'adequate' (31.4 wt% linoleic acid) or 'deficient' (2.7 wt% linoleic acid) diet, each lacking 20:4n-6 and DHA. [1-(14) C]DHA was infused intravenously, arterial blood was sampled, and the brain was microwaved at 5 min and analyzed. Rats fed the n-6 PUFA deficient compared with adequate diet had significantly reduced n-6 PUFA concentrations in brain phospholipids but increased eicosapentaenoic acid (EPA, 20:5n-3), docosapentaenoic acid n-3 (DPAn-3, 22:5n-3), and DHA (by 9.4%) concentrations, particularly in ethanolamine glycerophospholipid (EtnGpl). Incorporation rates of unesterified DHA from plasma, which represent DHA metabolic loss from brain, were increased 45% in brain phospholipids, as was DHA turnover. Increased DHA metabolism following dietary n-6 PUFA deprivation may increase brain concentrations of antiinflammatory DHA metabolites, which with a reduced brain n-6 PUFA content, likely promotes neuroprotection and alters neurotransmission.
| S-EPMC3296886 | biostudies-literature
Project description:The cancer chemopreventive agent ellagic acid (EA) is a known inhibitor of glutathione S-transferases (GSTs) and possesses antiplasmodial activities in the upper-nanomolar range. In the recent drug development approach, the properties of the active site of Plasmodium falciparum GST were exploited for inhibitor design by introducing one or two additional hydroxyl groups into EA, yielding flavellagic acid (FEA) and coruleoellagic acid (CEA), respectively. Indeed, the inhibition of P. falciparum GST was improved with the increasing hydrophilicity of the planar polyaromatic ring system. Studying the effects of the two compounds on the central redox enzymes of Plasmodium revealed that glutathione reductase and thioredoxin reductase also are inhibited in the lower-micromolar range. Both compounds had strong antiplasmodial activity in the lower-nanomolar range and were particularly effective against chloroquine (CQ)-resistant P. falciparum strains. Neither FEA nor CEA showed cytotoxic effects on human cells. This was supported by negligible changes in transcript levels and enzyme activities of redox enzymes in human A549 cells upon treatment with the compounds. In Plasmodium, however, CEA treatment resulted in a marked downregulation of most antioxidant genes studied and impaired mainly the trophozoite stage of the parasites. In addition, EA, CEA, and FEA were found to strongly inhibit in vitro heme aggregation. In vitro and preliminary in vivo studies indicated that, compared to CQ, CEA is a slowly acting compound and is able to significantly improve the survival of Plasmodium berghei-infected mice. We conclude that FEA and CEA are promising antimalarial compounds that deserve to be studied further.
| S-EPMC2630624 | biostudies-literature
Project description:1. The metabolism of a group of flavonoid compounds related in structure to apigenin (4',5,7-trihydroxyflavone) and including apigenin, apiin, naringin, phlorrhizin, acacetin, kaempferol, robinin, chrysin, tectochrysin and 4',7-dihydroxyflavone, was studied both in vivo after oral administration to the rat, and in vitro in cultures of micro-organisms derived from the intestine of the rat. 2. The rat intestinal microflora is capable of effecting degradation of flavonoid compounds to metabolites observed in the urine after oral administration of the specific flavonoid. 3. All compounds possessing free 5- and 7-hydroxyl groups in the A ring and a free 4'-hydroxyl group in the B ring gave rise to ring-fission products, which included 4'-hydroxyphenylacyl derivatives. 4. On anaerobic incubation in a thioglycollate medium, intestinal micro-organisms can effect flavonoid-ring fission, cleavage of glycosidic bonds and the reduction of double bonds in the side chains of certain metabolites. 5. Two flavonoids (chrysin and tectochrysin) undergo hydroxylation in the 4'-position in vivo but not during incubation with the intestinal microflora in vitro. 6. Observations on the metabolism of other compounds substituted in the 4'-position, e.g. epiafzelechin, pelargonin and the isoflavones, genistein, biochanin A, daidzein and formononetin, by the intestinal microflora of the rat are also reported.
| S-EPMC1173909 | biostudies-other
Project description:1. The metabolism of a group of polyphenols related in structure to myricetin (3,5,7,3',4',5'-hexahydroxyflavone), including myricetin, myricitrin, 3,4,5-trihydroxyphenylacetic acid, delphinidin, robinetin, tricetin, tricin, malvin and 5,7-dihydroxy-3',4',5'-trimethoxyflavone, has been studied both in vivo after oral administration to the rat and in vitro in cultures of micro-organisms derived from the intestine of the rat. 2. It was shown that the rat intestinal microflora are able to degrade compounds of this group to the ring-fission products observed in urine after oral administration of the specific flavonoid. 3. All flavones and flavonols possessing free 5- and 7-hydroxyl groups in the A ring and a free 4'-hydroxyl group in the B ring gave rise to ring-fission products that included 3',5'-dihydroxyphenylacyl derivatives. 4. The metabolites 3,5-dihydroxyphenylacetic acid, 3-hydroxyphenylacetic acid, 3,5-dihydroxyphenylpropionic acid and 3-hydroxyphenylpropionic acid were isolated and identified by chromatographic and spectral methods. 5. On anaerobic incubation in a thioglycollate medium it was shown that intestinal micro-organisms can effect cleavage of glycosidic bonds, ring fission of certain flavonoid molecules showing 3',4',5'-trihydroxyphenyl substitution and dehydroxylation of certain flavonoid metabolites. 6. The urinary excretion of the metabolites 3,5-dihydroxyphenylacetic acid and 3-hydroxyphenylacetic acid was completely abolished when neomycin-treated rats were used.
| S-EPMC1174309 | biostudies-other