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At least 19 recordsLinked to original sources
PubMedDate not supplied

Effects of human diets on biotransformation enzyme activity and metabolic activation of carcinogens in rat liver.

We studied the effects of a complete human diet, based on mean consumption figures in The Netherlands, the heating of food, and the presence of vegetables and fruit in the diet on the drug metabolizing capacity of the rat liver and on metabolic activation of known carcinogens. Groups of five male and five female Wistar rats were given ad lib. one of six different diets for 3 months. Each diet contained 40 energy (E)% fat, 13 E% protein, 47 E% carbohydrate and 5% fibre (w/w). The diets were as follows: a control diet of semi-synthetic materials (A); a human diet of meat, bread and eggs without processing (B); diet B heated under usual household conditions (C); a diet representing a complete human meal including (summer) vegetables and fruit (D); diets consisting of winter vegetables (E) or summer vegetables (F) with fruit. Semi-synthetic components were added to diets B-F to achieve the desired composition. There were differences between male and female rats on the effects of the different diets on hepatic enzyme activity. In female rats, but not in males, ethoxyresorufin-O-deethylase activity was increased significantly (P less than 0.05) in groups C, D and E in comparison with the controls (group A). In male rats ethoxycoumarin-O-deethylase activity was enhanced in groups D, E and F, and glutathione-S-transferase was markedly induced in group F (P less than 0.01). In males, hepatic cytochrome P-450 was significantly (P less than 0.05) increased in groups B, C and E. There was no effect on aminopyrine-N-demethylase activity and almost no effect on UDP-glucuronyltransferase activity in either sex. Microsomes from rats fed heated food (C) markedly increased the mutagenicity of benzo[a]pyrene (B[a]P) in the Ames assay using Salmonella typhimurium strain TA98, in comparison with levels using microsomes from rats fed the raw food (B). Vegetables and fruit decreased B[a]P mutagenicity. All human diets except D decreased the mutagenicity of N-nitrosodimethylamine in tester strain TA100. The results indicate that the influence of components of human diets on rat-liver drug metabolism may have quite different effects on the biotransformation of carcinogens activated by different metabolic pathways.

Animals↗
PubMed1986

[Need for rheologically active, vasoactive and metabolically active substances in the initial treatment of acute acoustic trauma].

Two rheologically active and 8 vasoactive and metabolically active substances were compared in eight independent studies, some of which were randomised and double blind, on 400 patients who had suffered acute acoustic trauma. The control group was given saline. Spontaneous recovery was excluded as far as possible. The following substances were tested: Dextran 40, hydroxyethyl starch 40/0.5, naftidrofurylhydrogenoxalate, Vinpocetin, betahistine, pentoxifylline, flunaricine, Regeneresen AU 4 and 0.9% saline. All groups showed superior results to the control group in both long-term and short-term tests with respect to hearing gain and tinnitis improvement. The rheologically effective substances showed no statistically significant variations. None of the vasoactive or metabolically active substances used as adjunctive therapy improved the results achieved with rheologically effective substances alone. These results demonstrate that acute acoustic trauma can be most effectively treated by rheologically active substances; vasoactive and metabolically active substances are unnecessary. Hyperbaric oxygenation is advantageous as an adjunctive therapy.

Adult↗
PubMed1975

Effects of various cerebral metabolic activators on glucose metabolism of brain.

The effects of various metabolic activators on the glucose metabolism of the perfused cat brain have been investigated. (1) When the perfusion is done with the blood containing cytidine monophosphate, the glucose metabolism of the brain is enhanced, as compared to the perfusion with the blood without cytidine monophosphate. There is no marked change in the cerebral metabolic rate and in the contents of intermediate metabolite of glucose in the brain. (2) Citicoline enhances the incorporation of blood glucose into the brain and its metabolism in the brain. It increases slightly the cerebral blood flow rate and decreases the accumulation of lactate in the brain. (3) Either Pyrithioxin or Meclophenoxate has no effect on the glucose metabolism of the brain nor on the cerebral metabolic rate.

Animals↗
PubMedDate not supplied

In vitro effects of an acyltripeptide, FK565, on antitumor effector activities and on metabolic activities of human monocytes and granulocytes.

In vitro effects of an immunostimulatory acyltripeptide, FK565, on antitumor and metabolic activities of human leukocytes were studied. Monocyte cytotoxicity against A375 melanoma targets was significantly increased following pretreatment with FK565 at concentrations of 1 microgram/ml or more. The tripeptide also up-regulated anti-tumor cytostasis by monocytes and showed a strong stimulatory effect on superoxide generation by resting monocytes over a wide range of FK565 concentrations after 18 h preincubation. The monocyte preparations contained an average of 76% LeuM3+HLA-DR+, 12% LeuM3+HLA-DR- and 10% LeuM3-HLA-DR+ cells, and this phenotype distribution was not altered after incubation with FK565. At concentrations above 1 microgram/ml and after 2 h preincubation, FK565 also increased superoxide generation by resting but not stimulated granulocytes. Pre-exposure of cultured bovine endothelial cells to the peptide resulted in a significant inhibition of fMLP-stimulated granulocyte adherence to these cells. These data indicate that in vitro incubation of human monocytes and granulocytes with FK565 (0.1-100 micrograms/ml) had resulted in simultaneous up-regulation of several anti-tumor functions mediated by these cells.

Adjuvants, Immunologic↗
PubMed1987

Regular stripe-like activation and suppression of metabolic activity in the cerebellar cortex following apomorphine administration to haloperidol-pretreated rats.

Alteration of the pattern of metabolic activity in the cerebellar cortex, as produced by apomorphine in rats given chronic pretreatment with haloperidol was studied by means of the [14C]deoxyglucose method. Apomorphine induced a regular stripe-like activation and suppression of metabolic activity in the caudal paravermal area of the cerebellar hemisphere and in the caudal vermis of the cerebellar cortex. This stripe-like pattern, oriented perpendicularly to the cerebellar fissure, suggests the functional organization of the cerebellar cortex in a direction which is parallel to the longitudinal axis of folia.

Animals↗
PubMed1990

Metabolic activation of natural phenols into selective oxidative burst agonists by activated human neutrophils.

Phenols isolated from the traditional medicinal plant Picrorhiza kurroa inhibit the release of superoxide anion (O2-) by activated human neutrophils, but leave the phagocytotic capacity intact. Resting neutrophils and resting or activated human lymphocytes are insensitive to these agents. The underlying mechanism of this highly selective activity is investigated. A critical event is the reaction of the phenols with secretory products from the activated neutrophils. The reaction products interfere with the assembly of a functional NADPH-oxidase in the membrane. Analysis of the mode of activation of the phenols reveals two possible pathways. Catechols react directly with reactive oxygen species (ROS) from the oxidative burst. For the activation of the orthomethoxy-substituted catechols the combined activity of ROS and myeloperoxidase (MPO) is obligatory. Catechols with a dimethoxy substitution cannot be activated metabolically by neutrophil-derived ROS.

Biotransformation↗
PubMed1992

Metabolic activity in inflammatory and non-inflammatory aneurysms of the abdominal aorta.

Inflammatory aneurysms of the abdominal aorta (IAA) comprise 10-15% of all aortic aneurysms (AA) but their aetiology and pathogenesis are obscure. Destruction of mural elastin is a prominent feature of IAA, and both increased elastolysis and decreased inhibition of elastolysis have been implicated. In order to study these factors, we have examined the peripheral blood of three groups of patients; 15 with inflammatory aortic aneurysms (IAA), 61 with simple aortic aneurysms (SAA) and 35 with aorto-iliac occlusive disease (OD). In all cases, alpha-1-anti-trypsin (A-1-AT), alpha-2-macroglobulin (A-2-MG), elastase inhibitory activity (E.I.A.), elastase-anti-trypsin complex, C-reactive protein (CRP), caeruloplasmin (CP) and plasma viscosity were measured. Patients with IAA had a significantly higher plasma viscosity (Mann-Whitney, p less than 0.05), E.I.A. (Mann-Whitney, p less than 0.01) and levels of A-1-AT, CRP, CP and elastase/anti-trypsin complex (Mann-Whitney, all p less than 0.05) than patients in the other two groups. There was no difference in the levels of A-2-MG between any of the groups. This study refutes the theory that reduced inhibition of elastase activity predisposes to the formation of SAA. In patients with IAA, raised marker levels indicate ongoing destruction of elastin, and suggest a difference in pathogenesis between IAA and SAA. The study also suggests that IAA are highly active metabolically, as opposed to the more degenerative SAA.

Acute-Phase Proteins↗
PubMed1985

Quantum chemical and other theoretical studies of carcinogens, their metabolic activation and attack on DNA constituents.

We have carried out a variety of different types of studies on carcinogens: ab-initio quantum chemical, including generation of electrostatic molecular potential contour (EMPC) maps and graph theoretical generation of polycyclic aromatic hydrocarbon (PAH) structures and characterization of the "carcinogenic" bay regions. Polycyclic aromatic hydrocarbon (PAH) carcinogens are activated metabolically from precarcinogen (PAH's) through proximate carcinogens (PAH epoxides and dihydrodiols) to ultimate carcinogens (PAH dihydrodiolepoxides) which then attack DNA constituents. We carried out ab-initio MODPOT/VRDDO/MERGE calculations on a variety of these molecules using our own ab-initio programs which incorporate as options a number of desirable options for ab-initio calculation on large molecules. From these electronic wave functions, we generated electrostatic molecular potential contour (EMPC) maps around these molecules. These EMPC maps indicated predictively the positions at which epoxides would form and the propensity and geometrical preference to form dihydrodiols and dihydrodiolepoxides. We performed spin and symmetry analyses for attack of O adding across C = C bonds or inserting in C-H or N-H bonds. We also carried out ab-initio calculations for attack of ultimate carcinogens on DNA constituents. Using graph theory we generated all possible structures for any arbitrary numbers of aromatic rings and also set up a graph theoretical characterization of the "carcinogenic" bay region. Most recently, we have incorporated this into a computer program for global prediction of toxicity.

Biotransformation↗
PubMed1988

The essential role of microsomal deacetylase activity in the metabolic activation, DNA-(deoxyguanosin-8-yl)-2-aminofluorene adduct formation and initiation of liver tumors by N-hydroxy-2-acetylaminofluorene in the livers of infant male B6C3F1 mice.

Deacetylation of N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) to N-hydroxy-2-aminofluorene (N-hydroxy-AF) has been proposed as one of the critical metabolic steps in the formation of hepatic DNA adducts and the initiation of liver tumors in 12-day-old male B6C3F1 mice. In this study, the importance of the microsomal deacetylase activity for N-hydroxy-AAF in the initiation of hepatocarcinogenesis in these mice was demonstrated by using a carboxylesterase and amidase inhibitor, bis(p-nitrophenyl)phosphate (BNPP), that is much less toxic in vivo than is paraoxon. Pre-incubation of liver microsomes from 12-day-old male B6C3F1 mice with 10(-3) M BNPP reduced the deacetylase activity by 80% while paraoxon inhibited the deacetylase activity completely at a concentration of 10(-4) M. Pretreatment of 12-day-old male B6C3F1 mice with 4 X 75 micrograms doses of BNPP/g body weight before the administration of N-hydroxy-AAF reduced the hepatic N-(dGuo-8-yl)-AF adduct levels to 1.09 and 0.68 pmol/mg DNA compared with 2.87 and 1.64 pmol/mg DNA for mice treated once with 0.06 or 0.03 mumol of N-hydroxy-AAF/g body weight respectively. However, BNPP pretreatments did not affect the levels of the acetylated DNA adducts, N-(dGuo-8-yl)-AAF and 3-(dGuo-N2-yl)-AAF, formed by these doses of N-hydroxy-AAF. The initiation of liver tumors by N-hydroxy-AAF was also inhibited by BNPP pretreatment. Thus, for mice that received single doses of 0.12, 0.06 and 0.03 mumol of N-hydroxy-AAF/g body weight, the multiplicities of liver tumors at 10 months were reduced by BNPP pretreatments to 5.6, 1.0 and 0.3 compared with multiplicities of 11.8, 4.8 and 1.7 without pretreatment respectively. On the other hand, BNPP pretreatments had no significant inhibitory effects on the levels of the hepatic DNA-N-(dGuo-8-yl)-AF adduct or on the liver tumor multiplicities induced by comparable doses of N-hydroxy-AF. It is concluded that deacetylation of N-hydroxy-AAF to N-hydroxy-AF is essential for the metabolic activation, DNA-N-(dGuo-8-yl)-AF adduct formation and liver tumor initiation in infant male B6C3F1 mice by N-hydroxy-AAF.

2-Acetylaminofluorene↗
PubMed1992

Use of a newly developed tester strain Salmonella typhimurium NM2009 for the study of metabolic activation of carcinogenic aromatic amines by rat liver microsomal cytochrome P-450 enzymes.

Using an O-acetyltransferase-overexpressing strain Salmonella typhimurium NM2009 we measured the activities for metabolic activation of several carcinogenic arylamines to genotoxic products by rat liver microsomal cytochrome P-450 enzymes, and compared them with the activities obtained in the original tester strain Salmonella typhimurium TA1535/pSK1002 or the O-acetyltransferase-defective strain Salmonella typhimurium NM2000. Since all of the tester strains had introduced the umuC'-'lacZ gene, we could detect the genotoxic activities by measuring bacterial beta-galactosidase activity resulting from the DNA damage. In the O-acetyltransferase-defective strain NM2000 most of the arylamines tested showed weak responses in inducing umu gene expression after metabolic activation by liver microsomes. The strain NM2009, on the other hand, was found to be highly sensitive towards a variety of aromatic amines, and these activities were greater than those seen in the original tester strain S. typhimurium TA1535/pSK1002. The chemicals which marked responses in strain NM2009 include 2-aminoanthracene, 6-aminochrysene, 2-aminofluorene, 2-acetylaminofluorene, 3-methoxy-4-aminoazobenzene, O-aminoazotoluene, Glu-P-1, Trp-P-2, A alpha C, MeA alpha C, MeIQ, MeIQx and IQ. Of these procarcinogens tested MeIQ, MeIQx and IQ also showed strong cytotoxic effects in S. typhimurium NM2009 after metabolic activation by liver microsomes. Only PhIP was the substrate showing similar responses in strains TA1535/pSK1002 and NM2009. The results with the reconstituted monooxygenase system containing purified cytochrome P-450 enzymes support the above findings obtained with the liver microsomal enzyme system. Thus, the usefulness of the newly developed strain NM2009 for the detection of reactive metabolites of several carcinogenic aromatic amines after metabolism by the liver microsomal cytochrome P-450-linked monooxygenase system has been ascertained.

Amines↗
PubMed1990

MAO activity, metabolism and anticonvulsant activity of milacemide in rats and mice.

Milacemide was found to protect Swiss albino CD1 mice but not Sprague Dawley rats against bicuculline-induced lethality. Since it had been previously suggested that the anticonvulsant activity of milacemide might be related to MAO-B- mediated glycine formation, brain and liver MAO-A and-B activities and the urinary metabolic pattern of milacemide were determined in the same mice and rat strains. Similar brain and liver MAO activities were found in the two species, except for liver MAO-A activity which was higher in rats. After the same oral dose of milacemide, the percent of the dose excreted as glycinamide was significantly higher in mice than in rats, whereas that excreted as metabolite UK1 was significantly higher in rats. These results support the hypothesis of a glycine-mediated anticonvulsant activity for milacemide and suggest that the increased formation of UK1 to the detriment of glycinamide might account for the lack of protection against bicuculline-induced lethality by milacemide in rats.

Acetamides↗
PubMed1985

Major role of hepatic sulfotransferase activity in the metabolic activation, DNA adduct formation, and carcinogenicity of 1'-hydroxy-2',3'-dehydroestragole in infant male C57BL/6J x C3H/HeJ F1 mice.

1'-Hydroxy-2',3'-dehydroestragole is a synthetic acetylenic analogue of 1'-hydroxyestragole, the proximate carcinogenic metabolite of the naturally occurring hepatocarcinogen estragole (1-allyl-4-methoxybenzene). This analogue is considerably more potent than 1'-hydroxyestragole as an hepatocarcinogen in mice. 1'-Acetoxy-2',3'-dehydroestragole reacted readily with deoxyguanosine or deoxyguanosine 5'-monophosphate at neutrality to form two adducts. Adduct I, isolated and characterized after dephosphorylation of the deoxyguanosine 5'-monophosphate product, was a 1:1 mixture of two diastereomers of N2-(2',3'-dehydroestragol-1'-yl)deoxyguanosine. Adduct II was shown to be N-7-(2',3'-dehydroestragol-1'-yl)guanine. The reaction of deoxyadenosine with 1'-acetoxy-2',3'-dehydroestragole at neutrality produced Adducts III and IV. Adduct IV was characterized as N6-(2',3'-dehydroestragol-1'-yl)deoxyadenosine. Administration of [1'-3H]-1'-hydroxy-2',3'-dehydroestragole to male preweanling C57BL/6J x C3H/HeJ F1 (hereafter called B6C3F1) mice resulted in extensive covalent binding to hepatic DNA, RNA, and protein. On hydrolysis of the DNA to nucleosides, a single major adduct accounted for greater than 85% of the DNA-bound 3H. This adduct comigrated with Adduct I in two high performance liquid chromatography systems, had a pH partition profile identical to that of Adduct I, and was present as a mixture of diastereomers in a ratio of 2:1. The identity of the DNA adduct formed in vivo with Adduct I from the reaction of 1'-acetoxydehydroestragole indicated that a reactive ester was a major metabolic precursor in vivo. There was no significant loss of Adduct I from the hepatic DNA by 21 days after a single injection of a carcinogenic dose of 1'-hydroxy-2',3'-dehydroestragole. Adducts II, III, and IV were not detected in significant amounts in the hepatic DNA isolated by a phenol extraction method or by a more rapid hydroxylapatite method. Cytosolic sulfotransferase activity was demonstrated for 1-hydroxy-2',3'-dehydroestragole in mouse liver, and inhibition of this activity by greater than 95% was found on addition of 10 microM pentachlorophenol. The administration of pentachlorophenol (0.04 mumol/g body weight) 45 min prior to a single dose of 1'-hydroxy-2',3'-dehydroestragole (0.04 mumol/g body weight) in 12-day-old male B6C3F1 mice greatly inhibited (87-97%) the covalent binding of 1'-hydroxy-2',3'-dehydroestragole to hepatic macromolecules and the formation of hepatomas at 10 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1976

Neutron-activation measurement of metabolic activity of sodium in the human hand.

Turnover of sodium in the human hand was studied by neutron activation. One hand of each subject was irradiated with a 1.5-rad dose of partially thermalized fast neutrons. The activity of 24Na was measured at intervals from 3 min to 48 hr after irradiation. The loss of sodium from the hand during this period can be described either by two exponentials or by a single power function. The latter description involves only two disposable factors compared with four in the former. The rate of loss of sodium was found, on the average, to be greater in patients suffering from bone disease than in normal subjects. Neutron activation is a powerful method for studying sodium turnover because the sodium atoms are labeled simultaneously and with equal probability, regardless of the turnover time of individual bodily compartments.

Adult↗
PubMed1986

Kinetic determination of enzymatic activity and modification of the metabolic activation system in the SOS chromotest.

The "SOS Chromotest" has recently been introduced by P. Quillardet et al. (1982; Quillardet and Hofnung, 1985), who use strain PQ37 of Escherichia coli K12 to test for genotoxicity. We have modified the procedure in order to optimize the determination of beta-galactosidase and alkaline phosphatase activities, and, where possible, to allow measurements to be made automatically. Kinetic determination is quicker, more sensitive and avoids interference by coloured compounds. Modification of the metabolic activation system increases the sensitivity of the test for progenotoxicity.

Alkaline Phosphatase↗
PubMed1989

A rapid in vitro method for the evaluation of potential antitumor drugs requiring metabolic activation by hepatic S9 enzymes.

Metabolic activation is a prerequisite for the antitumor activity of certain drugs such as cyclophosphamide. In vitro assays require systems for metabolic activation to reveal the toxicity of such compounds for tumor cells. Although a number of methods utilizing systems for the in vitro metabolic activation of drugs have been published, practical assays applicable to large scale screening for such agents have been lacking. We, therefore, now report that incorporation of a liver subcellular fraction (S9) into a recently established cell growth inhibition assay (microculture tetrazolium assay) significantly increased the cytotoxicity of cyclophosphamide. Under optimal conditions, the 50% growth inhibitory concentration was decreased in the presence of S9 from more than 600 micrograms/ml to less than 4 micrograms/ml, depending upon the cell line. The method also proved suitable for studies investigating metabolic detoxification (enzymatically or non-enzymatically) by conjugation reactions. For example, glutathione (5 mM) markedly reduced the cytotoxicity of activated cyclophosphamide. In contrast, the addition of UDP glucuronate (10 mM) in the presence of the UDP-glucuronosyltransferase activator UDP-N-acetylglucosamine (10 mM) had little effect on cyclophosphamide toxicity.

Animals↗
PubMed1979

Mediated mutagenesis of dimethylnitrosamine in Neurospora crassa by various metabolic activation systems.

Four metabolic activation systems (growth mediated mycelium extract mediated, host mediated, and organ homogenate mediated) were used to study the mutagenic activity of dimethylnitrosamine (DMN) in both forward and reverse mutation systems in the ad-3 (adenine-3) region of Neurospora crassa. DMN was not mutagenic in Neurospora if conidia alone were treated. It was highly mutagenic, however, if conidia were treated with this compound under any of the four activation systems. Quantitative differences in DMN-induced mutation frequencies were observed between in vivo (growth and host mediated) and in vitro (mycelium extract and organ homogenate mediated) activations. The efficiency of the conversion of DMN to a mutagenic metabolite by the organs of rats and mice appeared to be in a reversed order between the host-mediated (liver greater than kidney greater than lung) and the in vitro organ homogenate-mediated (lung greater than kidney greater than liver) assays. Inductions of reverse mutations in strain N23 indicated that DMN induces base-pair substitution in N. crassa.

Animals↗