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Biomedical subjects

J C Larsen

Publications and source records attributed to J C Larsen.

At least 37 records · Page 2Linked to original sources
PubMed1994

Formation of DNA adducts by the food mutagen 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx) in vitro and in vivo. Identification of a N2-(2'-deoxyguanosin-8-yl)-4,8-DiMeIQx adduct.

The covalent binding of the mutagenic N2-hydroxy metabolite of the food mutagen 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx) to 2'-deoxynucleosides and DNA was investigated in vitro and in vivo. N2-Hydroxy-4,8-DiMeIQx reacted to a small extent spontaneously with 2-deoxyguanosine. However, acetylation of N2-hydroxy-4,8-DiMeIQx with acetic anhydride to form the N2-acetoxy derivative prior to reaction with 2-deoxyguanosine resulted in much higher yield of adduct. N2-Acetoxy-4,8-DiMeIQx did not form adducts with 2'-deoxyadenosine, 2'-deoxycytidine or 2'-deoxythymidine. The adduct formed between the N2-OH metabolite of 4,8-DiMeIQx and 2-deoxyguanosine was analysed by mass spectrometry and NMR spectroscopy and the structure of the adduct was shown to be N2-(2'-deoxyguanosin-8-yl)-4,8-DiMeIQx. N2-Acetoxy-4,8-DiMeIQx reacted with calf thymus DNA and formed a covalently bound 4,8-DiMeIQx residue, which could not be removed by repeated precipitations or solvent extractions. The 4,8-DiMeIQx-DNA was hydrolysed enzymatically with nuclease P1/acid phosphatase and HPLC analysis showed that 70% of the bound mutagen was recovered as N2-(2'-deoxyguanosin-8-yl)-4,8-DiMeIQx. An additional minor adduct accounting for approximately 15% of the bound mutagen showed UV spectral characteristics similar to N2-(2'-deoxyguanosin-8-yl)-4,8-DiMeIQx and is probably an undigested oligomer. 32P-Postlabelling analysis of calf thymus DNA modified with 4,8-DiMeIQx in vitro and liver DNA from rats dosed with 50 mg/kg 4,8-DiMeIQx showed a similar adduct pattern. In both samples N2-(2'-deoxyguanosin-8-yl)-4,8-DiMeIQx accounted for 60-70% of the bound mutagen. Thus, these results show that 4,8-DiMeIQx similar to other heterocyclic amines form adducts with C-8 of guanine both in vitro and in vivo via its N2-OH metabolite.

Acetylation↗
PubMed1994

Microsomal metabolism of the food mutagen 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]-quinoxaline to mutagenic metabolites.

Heterocyclic aromatic amines are formed in the crust of meat during ordinary cooking. These aromatic amines are potent bacterial mutagens and also potent rodent carcinogens. 2-Amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (DiMeIQx) is one of the more abundant heterocyclic aromatic amines, accounting for approximately 20% of the mutagenic material found in cooked meat. DiMeIQx is metabolically activated, by hepatic microsomes from PCB treated rats, to two major and three minor metabolites. One major and one minor metabolite were identified as 2-hydroxyamino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline and 3,4,8-trimethyl-2-nitro-3H-imidazo[4,5-f]quinoxaline, respectively, confirmed by comparison of HPLC retention times, and UV and mass spectra of synthetic standards. Both metabolites were mutagenic in Salmonella typhimurium TA98 without metabolic activation. The other major metabolite was identified as 2-amino-8-hydroxymethyl-3,4-dimethyl-3H-imidazo[4,5-f]quinoxaline by mass and NMR spectral analysis. The two remaining minor metabolites were identified as the 2-hydroxyamino- and 2-nitro- derivatives of 2-amino-8-hydroxymethyl-3,4-dimethyl-3H-imidazo]4,5-f]quinoxaline by UV and mass spectral analysis. Both of these metabolites were mutagenic in S. typhimurium TA98 without metabolic activation.

Animals↗
PubMed1993

Cancer-protective factors in fruits and vegetables: biochemical and biological background.

Cancer-protective factors are present in several fruits, vegetables and commonly used spices and herbs. They can be divided into several different groups, based on their chemical structure, e.g. polyphenols, thiols, carotenoids and retinoids, carbohydrates, trace metals, terpenes, tocopherols and degradation products of glucosinolates (i.e. isothiocyanates, indoles and dithiothiols) and others. Among each of these groups of compounds are substances, which may exert their cancer-protective action by more than one biochemical mechanism. The biochemical processes of carcinogenesis are still not known in detail and probably varies with the cancer disease in question. Accordingly, the description of the biochemical backgrounds for the actions of cancer-protective factors must be based on a simplified model of the process of carcinogenesis. The model used in this presentation is a generalised initiation-promotion-conversion model, in which initiators are thought to be directly or indirectly genotoxic, promoters are visualised as substances capable of inferring a growth advantage on initiated cells and converters are believed to be genotoxic, e.g. mutagens, clastogens, recombinogens or the like. Experimental evidence for the mechanisms of action of cancer-protective agents in fruits and vegetables that protect against initiation include the scavenging effects of polyphenols on activated mutagens and carcinogens, the quenching of singlet oxygen and radicals by carotenoids, the antioxidant effects of many compounds including ascorbic acid and polyphenols, the inhibition of activating enzymes by some flavonols and tannins, the induction of oxidation- and of conjugation (protective) enzymes by indoles, isothiocyanates and dithiothiones, the shielding of sensitive structures by some polyphenols and the stimulation of DNA-repair exerted by sulphur-containing compounds. Mechanisms at the biochemical level in anti-promotion include the antioxidant effects of carotenoids and the membrane stabilizing effects reported with polyphenols, the inhibition of proteases caused by compounds from soybeans, the stimulation of immune responses seen with carotenoids and ascorbic acid and the inhibition of ornithine decarboxylase by polyphenols and carotenoids. A few inhibitors of conversion have been identified experimentally, and it can be argued on a theoretical basis, that many inhibitors of initiation should also be efficient against conversion. The mechanisms of anticarcinogenic substances in fruits and vegetables are discussed in the light of cancer prevention and inhibition.

Animals↗
PubMed1992

Mutagenic activity of nine N,N-disubstituted hydrazines in the Salmonella/mammalian microsome assay.

The mutagenic activity of N,N-dimethyl-, N,N-diethyl-, N,N-dibutyl-, N,N-diisobutyl-, N,N-di(p-tolyl)-, N-ethyl-N-phenyl-, N,N-dibenzyl-, N,N-diphenyl- and N,N-diisopropylhydrazine was examined in the Salmonella/mammalian microsome assay using the strains TA1535, TA1537, TA97, TA98, TA100, TA102 and TA1530. All nine hydrazines were mutagenic in at least one tester strain, although of borderline significance for some of the compounds. The mutagenic potencies of the hydrazines varied 2-3 orders of magnitude, from very weak to moderate mutagenic activity. In general, the addition of S9 resulted in a lowering of the mutagenic activity and a lowering of the toxic properties of the hydrazines. The test results were relatively difficult to evaluate due to toxic effects of many of the test compounds on the test bacteria which may have resulted in an underestimation of the mutagenic potencies of some of the compounds. The pattern of mutagenic activity of the hydrazines in the different tester strains indicates that more than one mechanism of action may be involved in the mutagenicity.

Animals↗
PubMed1992

Reaction of the N2-acetoxy derivative of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) with 2'-deoxyguanosine and DNA. Synthesis and identification of N2-(2'-deoxyguanosin-8-yl)-PhIP.

The direct acting mutagenic N2-hydroxylated metabolite of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) does not react with DNA. Upon acetylation of the N2-hydroxy-PhIP with acetic anhydride two products could be detected. Mass spectrometric analysis showed that both products were monoacetyl derivatives of N2-hydroxy-PhIP. One of the products did not show any reactivity towards DNA and is probably the N-acetyl derivative of N2-hydroxy-PhIP. The other product which is most likely to be N2-acetoxy-PhIP reacted with DNA and 2'-deoxyguanosine but not with 2'-deoxycytidine, 2'-deoxyadenosine or 2'-deoxythymidine. The PhIP-2'-deoxyguanosine adduct was purified and characterized by mass spectral, 1H and [13C]NMR analysis, showing that PhIP like the other cooked food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, had reacted with C-8 of guanine forming N2-(2'-deoxyguanosin-8-yl)-PhIP. HPLC analysis of enzymatically hydrolyzed calf thymus DNA which had been reacted with N2-acetoxy-PhIP showed one adduct which was chromatographically and spectroscopically identical to N2-(2'-deoxyguanosin-8-yl)-PhIP. HPLC separation followed by liquid scintillation counting of hydrolyzed liver DNA from a rat dosed with [3H]PhIP showed that radioactivity coeluted with the hydrolysis product of the synthetic PhIP-2-deoxyguanosine adduct, indicating that PhIP in vivo also forms an N2-(2'-deoxyguanosin-8-yl)-PhIP adduct.

Animals↗
PubMed1991

Metabolic formation, synthesis and genotoxicity of the N-hydroxy derivative of the food mutagen 2-amino-1-methyl-6-phenylimidazo (4,5-b) pyridine (PhIP).

Hepatic microsomes from rats pretreated with PCB were found to metabolize the food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) to two major metabolites, one of which was identified as the N-hydroxy derivative, 2-hydroxy-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (N-OH-PhIP). This identification was based on mass spectral (MS), UV and HPLC data by comparison with N-OH-PhIP prepared by chemical synthesis, as well as the specific activity of the compound in the Ames Salmonella test. Synthetic N-OH-PhIP was prepared by catalytic reduction of the nitro derivative of PhIP, which was synthesized from PhIP by diazotization and reaction with sodium nitrite. N-OH-PhIP was mutagenic to Salmonella typhimurium TA98 without metabolic activation and had a specific mutagenic activity of 2700 revertants/nmol. N-OH-PhIP thus seems to be a proximate mutagenic metabolite of PhIP. Other direct acting mutagens were not detected in the microsomal incubation mixture after HPLC separation. N-OH-PhIP also induced sister chromatid exchange (SCE) in Chinese hamster ovary cells (CHO cells) without metabolic activation. The specific activity of N-OH-PhIP in this assay was approximately 3 times higher than the activity of PhIP with microsomal activation.

Animals↗
PubMed1988

Teratogenicity and in vitro mutagenicity studies on nonoxynol-9 and -30.

Polyoxyethylene alkylphenols (PA) are a group of non-ionic surfactants with a widespread use. As part of the safety evaluation of PA a teratology study with nonoxynol-9 and -30 (NP-9 and NP-30) administered perorally and epicutaneously to rats was performed. In addition the mutagenicity of NP-9 was tested in the Ames test. Treatment of pregnant rats with NP-30 (up to 1 g/kg b.wt./day, orally) did not reveal any signs of adverse effects. Pregnant rats given 250 mg or 500 mg NP-9/kg b.wt./day orally exhibited a statistically significant decrease in weight gain. A concomitant effect in these dams on reproduction, and an increase in the incidence of extra ribs and dilated pelvic cavity in their foetuses was interpreted as a consequence of a toxic effect of high doses of NP-9. No clear cut effect was observed when pregnant rats were dosed epicutaneously with up to 500 mg of NP-9/kg b.wt./day. A slight but persistent response in one tester strain in the Ames test was not interpreted as a clear mutagenic effect of NP-9.

Animals↗
PubMed1985

Subchronic oral toxicity of turmeric oleoresin in pigs.

Turmeric oleoresin was fed for 102-109 days to groups of eight pigs (males and females) at dietary levels providing intakes of 60, 296 and 1551 mg/kg body weight/day. Twelve pigs served as controls. The highest dose group showed a reduction in weight gain and in food-conversion efficiency. Statistically significant dose-related increases in the weight of the liver and the thyroid were recorded at all dose levels. Pericholangitis, hyperplasia of the thyroid and epithelial changes in the kidney and urinary bladder were observed in the two higher dose groups. It is questionable whether a no-adverse-effect level can be established on the basis of the observations in this experiment. Further studies should be initiated to elucidate the mechanism of action of turmeric.

Administration, Oral↗
PubMed1985

Effect of subcutaneous salbutamol on postoperative pulmonary function in patients undergoing elective cholecystectomy.

In a double-blind study, 14 patients underwent elective cholecystectomy. The patients were randomly allocated to two groups of seven to receive either s.c. salbutamol 0.5 mg or placebo 0.5 mg immediately before extubation and every 6 h for 48 h. In the placebo group there was a significant reduction in mean arterial oxygen tension of seven patients 3, 27 and 51 h after surgery (P = 0.006, P = 0.01 and P = 0.02) compared with the mean value before operation. The reduction in mean arterial oxygen tension in the group receiving salbutamol was not significant 3 h after surgery (P = 0.13), whereas reduction was significant 27 and 51 h later (P = 0.01 and P = 0.02) compared with the mean value before operation. Mean arterial oxygen tension was significantly higher in the salbutamol group than in the placebo group 3 h after operation (P = 0.03), whereas it was not significant 27 and 51 h later (P = 0.48 and P = 0.55). Mean spirometric values showed significant reductions 27 and 51 h after operation in both groups compared with the pre-operative measurements. Smaller insignificant differences were found between the salbutamol and placebo groups 27 and 51 h after operation. However, mean FEV1 in the salbutamol group 51 h after operation was 22% higher in comparison with the placebo group. Our results suggest that salbutamol may reduce postoperative hypoxaemia during the first few hours after the operation, but not later on.

Adult↗
PubMed1981

Immunogenicity of some common thermolabile surface antigens of Escherichia coli.

The development in rabbits of antibodies against common thermolabile Escherichia coli surface antigens - and against O and K antigens - was investigated. Three strains, E3b (O75:K95:H5), E56b (O8:K27:H-), and H61 (O45:K1:H10), and five rabbits per strain were used. Immunization was carried out by routine procedures using non-heated whole cell vaccines. Homologous and heterologous reactions were recorded. Bacterial agglutination showed no great differences between homologous antisera. Maximum agglutination titers were reached after three immunizations, i.e., 12 dyas after the first immunization. The development of antibodies to the many single common and specific antigens was followed by examination in crossed immunoelectrophoresis (CIE). Indication of immune tolerance of polysaccharide K27 antigen was found. The finding of pre-immune antibody and the rapid response to immunization indicate that many of the reactions recorded should be regarded as secondary responses. Several antigens in the three strains were identical or serologically related. The common cross-reacting thermolabile surface antigens showed similar electrophoretic mobility in the three stains. Some rabbits were found to be overall good producers of antibodies and some were poor. The occurrence or absence of pre-immune antibody to common antigens could not be sued to select the good antibody producers. It is suggested that the immune response to the common surface antigens that could be reckoned as outer membrane proteins may influence the relationship between host and bacterium.

Agglutination Tests↗
PubMed1980

Crossed immunoelectrophoresis and chemical structural analysis used for characterization of two varieties of Escherichia coli K2 polysaccharide antigen.

Crossed immunoelectrophoresis has shown that the Escherichia coli polysaccharide K2 antigen exists in two forms, K2ab and K2a. In confirmation of this finding, chemical structural analysis showed that K2ab, in addition to the galactose, glycerol and phosphate groups common to K2ab and K2a, contained 0 acetyl groups. The contrast between the earlier and the present K2 designation is discussed and the superiority of the CIE technique for this type of analysis is underlined.

Escherichia coli↗
PubMed1978

Hypersensitivity reactions to food colours with special reference to the natural colour annatto extract (butter colour).

It is well known that synthetic food colours especially some azo dyes can provoke hypersensitivity reactions such as urticaria, angioneurotic oedema, and astma (Michaëlsson and Juhlin, 1973, Granholt and Thune, 1975). Natural food colours are scarcely investigated with respect to potential allergic properties. Annatto extract, a commonly used food colour in edible fats e.g. butter, has been tested in patients. Among 61 consecutive patients suffereing from chornic urticaria and/or angioneurotic oedema 56 patients were orally provoked by annatto extract during elimination diet. Challenge was performed with a dose equivalent to the amount used in 25 grammes of butter. Twentysix per cent of the patients reacted to this colour 4 hours (SD: 2,6) after intake. Similar challenges with synthetic dyes showed the following results: Tartrazine 11%, Sunset Yellow FCF 17%, Food Red 17 16%, Amaranth 9%, Ponceau 4 R 15%, Erythrosine 12% and Brillant Blue FCF 14%. The present study indicates that natural food colours may induce hypersensitivity reactions as frequent as synthetic dyes.

Angioedema↗
PubMed1978

Stimulation of DNA synthesis in mouse and rat lung following administration and butylated hydroxytoluene.

Butylated hydroxytoluene (BHT) is a widely used antioxidant in food. It has recently been reported that intraperitoneal injection of BHT to female mice produced, within 3-5 days, a hypertrophy, hyperplasia, and general disorganisation of the cellular components of the lung (Marion and Mitchell, 1972). In male mice it was shown that this effect of BHT was associated with a marked stimulation of DNA synthesis in the lung (Witschi and Saheb, 1974). Measuring the incorporation of thymidine-2-14C into DNA in lung confirmed the results reported in mice. 500 mg of BHT per kg, i.p., resulted in a 20-40 fold increase in thymidine incorporation in both male and female mice after 4 days. In similar experiments in the rat, however, a two-fold increase was observed in female rats, no effect could be demonstrated in male rats. In experiments in male and female mice using p.o. administration of BHT similar results have been obtained as following i.p. administration.

Animals↗
PubMed1978

Absorption and excretion of 1-amino-2-naphthol-6-sulphonic acid in rats and rabbits.

1-amino-2-naphthol-6-sulphonic acid (ANSA) and compounds of similar structure are metabolites formed by azo reduction in mammals from several commonly used food colours, e.g. Sunset Yellow FCF and Food Red 17. At our institute it has been shown that ANSA produces bile duct proliferation when given orally to rabbits. Furthermore Orange RN which by azo reduction yields ANSA (and aniline) induce the same effect in pigs (Olsen et al., 1973) but not in rats (Gaunt et al., 1971). Using 35S-labelled ANSA the absorption and excretion as well as the localisation in the liver cell of ANSA was investigated in rats and rabbits. The results after p.o. administration shows that the rabbit absorbs and excretes into the urine a significant larger amount of ANSA (30-40%) than the rat (6-13%). The results after i.v. administration shows that some 60% of the injected dose is excreted in the urine in both species. In the rat 15-20% are recovered from the faeces, while only traces (0.1-0.5%) are found in faeces of rabbits. A significant amount of ANSA was retained in the blood and the liver of both species 24 and 48 hours after administration. After differential centrifugation of liver homogenates the majority of ANSA was found in the 9000 x g supernatant.

Absorption↗
PubMed1978

Hemiglobin formation in vitro induced by azo dyes and their metabolites.

Azo dyes which after reduction by the intestinal flora yield aniline are known as inducers of Heinz bodies after oral intake (J.J.-P. Drake, 1975). The effect of aniline is thought to depend on its metabolic conversion to the known hemiglobin inducers, phenylhydroxylamine and o- and p-aminophenol (A. de Bruin, 1976). The azo dyes used for colouring of foods are reduced in vivo forming sulphonated primary aromatic amines, many of which are of aminonaphthol structure. Such compounds could be potential hemiglobin inducers. This possibility was investigated in vitro by incubating the following azo dyes and their metabolites, with red cells in Krebs-Ringer phosphate solution: Chrysoin S, Scharlach GN, Azorubine, Sunset Yellow FCF, Food Red 17, Orange GGN, Ponceau 4R, Amaranth, Ponceau 6R and Fast Yellow AB. The concentration in the incubate was 0.5 mmol/l and the hemiglobin formation was measured after 1 h. The effect on red cells from pigs was compared with the effect on human red cells. Only the metabolites containing amino and naphthol groups together were active. The activity depended on the number and position of the sulfonic acid groups.

Animals↗