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Biomedical subjects

G Williamson

Publications and source records attributed to G Williamson.

At least 73 records · Page 4Linked to original sources
PubMed1998

Characterization of flavonoids as monofunctional or bifunctional inducers of quinone reductase in murine hepatoma cell lines.

The ability of flavonoid compounds to induce the activity of the phase II anticarcinogenic marker enzyme, quinone reductase (QR), has been studied in a wild-type murine hepatoma cell line (Hepalclc7) and in an Ah-receptor-defective mutant of the same cell line (Hepalclc7 bp(r)cl). The results showed that 10 (beta-naphthoflavone, kaempferide, tamarixetin, rhamnetin, quercetin, kaempferol, quercetin-4'-glucoside, isorhamnetin, daidzein and genistein) of the 13 flavonoids tested induced QR activity in the wild-type cells. Only the latter six also showed such activity in the bp(r)cl mutant, which indicates that they induce phase II enzymes directly (monofunctional inducers), whereas the others induce phase 11 enzymes only in cells with an operative Ah receptor system (bifunctional inducers). The metabolism of representatives of monofunctional (quercetin) and bifunctional (tamarixetin and rhamnetin) flavonol inducers were studied in both wild-type and bp(r)cl cells. In all cases, the major metabolites were glucuronides. Quercetin produced identical metabolites in both cell types, whereas one glucuronide of tamarixetin and two glucuronides of rhamnetin were not formed in the mutant cells. This shows that flavonoids can be mono- or bifunctional inducers depending on their chemical structure, and that the glucuronidation pattern of bifunctional inducers is altered by the presence of a functional Ah receptor system.

Animals↗
PubMed1998

Antioxidant properties of catechins and proanthocyanidins: effect of polymerisation, galloylation and glycosylation.

A range of catechins and oligomeric procyanidins was purified by high performance liquid chromatography (HPLC) from grape seed, apple skin, lentil and almond flesh. Catechins, galloylated epicatechin, glycosylated catechin, procyanidin dimers, galloylated dimers, trimer, and tetramer species were all identified, purified and quantified by HPLC, LC-MS and NMR. The antioxidant properties of these compounds were assessed using two methods: (a) inhibition of ascorbate/iron-induced peroxidation of phosphatidylcholine liposomes; (b) scavenging of the radical cation of 2,2'-azinobis(3-ethyl-benzothiazoline-6-sulphonate) (ABTS) relative to the water-soluble vitamin E analogue Trolox C (expressed as Trolox C equivalent antioxidant capacity, TEAC). Antioxidant activity in the lipid phase decreased with polymerisation in contrast with antioxidant action in the aqueous phase which increased from monomer to trimer and then decreased from trimer to tetramer. Galloylation of catechin and dimeric procyanidins decreased lipid phase and increased aqueous phase antioxidant activity. Glycosylation of catechin demonstrated decreased activity in both phases.

Anthocyanins↗
PubMed1998

Antioxidant effects of propofol in human hepatic microsomes: concentration effects and clinical relevance.

Propofol is known to possess antioxidant properties. There is controversy regarding the mechanisms by which the drug produces its antioxidant effects and the significance of these effects in relation to plasma concentrations of propofol in clinical practice. We studied the effects of increasing concentrations of Intralipid, propofol, butylated hydroxytoluene (BHT) and a vitamin E analogue (Trolox C) in 0.9% saline on non-enzymic and enzymic lipid peroxidation in human hepatic microsomes, and on concentrations of antioxidant enzymes in a Hep G2 cell line. Propofol showed significant inhibition of lipid peroxidation, but was less potent than BHT or Trolox C. IC50 values for non-enzymic and enzymic lipid peroxidation were mean 9.47 (SD 0.86) and 7.39 (0.84) mumol litre-1 for propofol, 1.30 (0.57) and 0.32 (0.02) mumol litre-1 for BHT and 2.34 (0.68) and 0.35 (0.04) mumol litre-1 for Trolox C, respectively. The antioxidant activities of propofol were substantially retained in the presence of up to 30 g litre-1 of human serum albumin. Propofol at concentrations of up to 100 mumol litre-1 had no significant effect on the activities of antioxidant enzymes. Clinically relevant concentrations of propofol produced significant inhibition of both enzymic and non-enzymic lipid peroxidation in hepatic microsomal preparations, possibly as a result of accumulation in lipophilic environments. Measurement of antioxidant effects of drugs in aqueous media may have little relevance to their effects in protecting against lipid peroxidation in biological systems.

Anesthetics, Intravenous↗
PubMed1998

Selective increase of the potential anticarcinogen 4-methylsulphinylbutyl glucosinolate in broccoli.

The putative anticarcinogenic activity of Brassica vegetables has been associated with the presence of certain glucosinolates. 4-Methylsulphinylbutyl isothiocyanate (sulphoraphane), derived from the corresponding glucosinolate found in broccoli, has previously been identified as a potent inducer of the anticarcinogenic marker enzyme quinone reductase [NADP(H):quinone-acceptor oxidoreductase] in murine hepatoma Hepa 1c1c7 cells. We have therefore produced a broccoli hybrid with increased levels of this anticarcinogenic glucosinolate and tested the ability of extracts to induce quinone reductase. A 10-fold increase in the level of 4-methylsulphinylbutyl glucosinolate was obtained by crossing broccoli cultivars with selected wild taxa of the Brassica oleracea (chromosome number, n = 9) complex. Tissue from these hybrids exhibited a >100-fold increase in the ability to induce quinone reductase in Hepa 1c1c7 cells over broccoli cultivars, due to both an increase in 4-methylsulphinylbutyl glucosinolate content and increased percentage conversion to sulphoraphane.

Anticarcinogenic Agents↗
PubMed1998

An expressional system of human cytochrome P-450 CYP1A1 gene transcription.

AIM: To explore an expressional system of human cytochrome P-450 CYP1A1 (CYP1A1) gene transcription. METHODS: The plasmid pMC 6.3 K containing human CYP1A1 promoter was transiently transfected into Hep G2 cells. The expression of chloramphenical acetyltransferase (CAT) reporter gene was detected by ELISA. RESULTS: Both the CAT expression and CYP1A1 activity increased with the concentrations of beta-naphthoflavone from 2.5 to 10 mumol.L-1. At 10 mumol.L-1 of beta-naphthoflavone, the levels of CAT and CYP1A1 were 94-fold and 2.8-fold those of the corresponding control, respectively. Using this method, the study of 8 glucosinolates with various side chains on the induction of CYP1A1 gene transcription showed that none of the parent glucosinolates increased CAT expression, whereas the breakdown products of indol-3-yl-methyl glucosinolate (glucobrassicin), rather than indole-3-carbinol, increased the CAT expression. CONCLUSION: The CYP1A1 gene transcriptional system was more reliable and sensitive.

Brassica↗
PubMed1998

Glucosinolates and phenolics as antioxidants from plant foods.

Dietary glucosinolates and flavonoids exhibit anticarcinogenicity by blocking formation of endogenous or exogenous carcinogens and so preventing initiation of carcinogenesis. Glucosinolates act by induction of antioxidant and detoxifying enzymes such as glutathione-S-transferases and UDP-glucuronosyl transferase, and by inhibition of carcinogen-activating enzymes such as cytochrome P450 1A1. Flavonoids and other phenolic antioxidants act by direct free-radical scavenging. The distribution in foods and structure-function relationships for these classes of compounds are reviewed.

Antioxidants↗
PubMed1997

Influence of ferulic acid on the production of feruloyl esterases by Aspergillus niger.

Extracellular feruloyl esterases from the filamentous fungus Aspergillus niger are induced by growth on oat spelt xylan (OSX), which contains no detectable esterified ferulic acid. FAE-III accounted for most of the feruloyl esterase activity. Addition of free ferulic acid to OSX at the start of the culture induced FAE-III secretion a further 2.3-fold, and also induced other feruloyl esterases which could not be ascribed to FAE-III. Wheat bran-(WB)-grown cultures, containing 1% (m/v) esterlinked ferulic acid, gave almost identical FAE-III and total feruloyl esterase activities as the cultures grown on OSX plus ferulic acid. De-esterification of WB yielded less total feruloyl esterase, and 2.4-fold less FAE-III, compared to untreated WB. A slightly modified form of FAE-III was produced on de-esterified WB. These results show that production of FAE-III does not absolutely require ferulic acid. However, production is stimulated by the presence of free ferulic acid through increased expression, and is reduced by the removal of esterified ferulic acid from the growth substrate.

Aspergillus niger↗
PubMed1997

Induction of the anticarcinogenic marker enzyme, quinone reductase, in murine hepatoma cells in vitro by flavonoids.

Some flavonoids induce phase II enzymes both in vivo and in vitro. We have determined the structural requirements for this activity by examining the ability of naturally-occurring flavonoids to induce the phase II enzyme, quinone reductase (NAD(P)H:quinone oxidoreductase; EC 1.6.99.2), in murine Hepalclc7 cells. Hydroxylation of the B ring is not essential for induction, since galangin and kaempferol (with 0 and 1 hydroxyl in the B ring, respectively) are better inducers than quercetin (2 B ring hydroxyls). A 2,3 double bond in the C ring is essential for induction, since taxifolin, which has the same substitution pattern as quercetin but lacks the 2,3 double bond, is not an inducer. This is supported by catechin and epicatechin, which do not possess the 2,3 double bond and are also not inducers. A 3-hydroxyl group increases the activity but is not essential for induction, since apigenin is an inducer but kaempferol (which has the same structure as apigenin but possesses a 3-hydroxyl group) is more effective. The data show that, of the flavonoids, the flavonols are the most effective inducers of quinone reductase activity in Hepa1c1c7 cells (kaempferol approximately galangin > quercetin > myricetin approximately apigenin (a flavone)) and that flavanols and flavans are ineffective.

Animals↗
PubMed1997

Methyl phenylalkanoates as substrates to probe the active sites of esterases.

We have used methyl esters of phenylalkanoic acids to probe the active site of two esterases (FAE-III and CinnAE) from Aspergillus niger. Only methyl 4-hydroxy-3-methoxycinnamate and 4-hydroxy-3-methoxyphenylpropionate out of 19 substrates tested were significant substrates for both enzymes (k(cat) values about 10(2) s(-1) and 10(3) s(-1), respectively). Lengthening or shortening the aliphatic side chain while maintaining the same aromatic substitutions completely abolished activity for both enzymes, which demonstrates the importance of the correct distance between the aromatic group and the ester bond. Differences in Km values for FAE-III were small (0.45-2.08 mM) but there were two orders of magnitude difference in k(cat) values (12.1-1063 s(-1)), whereas for CinnAE, there were large differences in values for both Km (0.014-1.32 mM) and k(cat) (41.3-1410 s(-1)). Lability of the ester bonds, as estimated from second-order rate constants (k2) for chemical reaction with sodium hydroxide, did not correlate to k(cat) for CinnAE (r = 0.33) or for FAE-III (r = 0.43). Maintaining the phenylpropenoate structure but altering the substitutions on the aromatic ring demonstrated the following: a 3-methoxy group is essential for FAE-III activity, whereas a 3-methoxy group precluded activity of CinnAE, with the exception of methyl 4-hydroxy-3-methoxycinnamate which was a relatively poor substrate for CinnAE; (b) increasing the number of methoxy substitutions increased the activity of FAE-III, and decreased the activity of CinnAE; (c) 4-hydroxy substituents, and additional hydroxy substituents, increased the activity of CinnAE, but decreased that of FAE-III; (d) the rate of hydrolysis with sodium hydroxide of the methyl esters in general is decreased by hydroxy substitutions on the aromatic ring but increased by methoxy substitutions. Analysis of kinetic data obtained in the presence of inhibitors indicated that substrate analogs were able to bind to both free CinnAE and to a CinnAE-substrate complex, but conversely, were only able to bind to free FAE-III. The results show that the specificities of the two A. niger esterases are complementary. The rate of hydrolysis by this class of carboxylic ester hydrolase does not depend on the intrinsic lability of the ester bond, but depends on both the distance between the aromatic ring and the ester bond, and the substitutions on the aromatic ring.

Aspergillus niger↗
PubMed1997

Reduction of thymine hydroperoxide by phospholipid hydroperoxide glutathione peroxidase and glutathione transferases.

Thymine hydroperoxide (5-hydroperoxymethyluracil), a model compound representing products of oxidative damage to DNA, is a substrate for glutathione peroxidase and some isoforms of glutathione transferase. In this paper, we show that selenium-dependent human phospholipid hydroperoxide glutathione peroxidase (Se-PHGPx) exhibits about four orders of magnitude higher activity on thymine hydroperoxide than that of other human enzymes such as selenium-dependent glutathione peroxidase and various representatives of glutathione transferases. The results indicate that Se-PHGPx may be an important enzyme in repairing oxidatively damaged DNA.

Animals↗