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PubMed1999

Ethanol pretreatment enhances NMDA excitotoxicity in biogenic amine neurons: protection by brain derived neurotrophic factor.

BACKGROUND: Biogenic amine neurons are involved in a number of mental diseases including addiction and alcohol dependence. Because chronic ethanol is known to cause supersensitivity to NMDA excitotoxicity in cortical neurons, this study sought to determine the effect of ethanol treatment on biogenic amine neurons. METHODS: To determine if ethanol exposure alters the vitality of biogenic amine neurons, cultures were prepared from E14 rat brain. After 24 hr in culture, cells were divided into control or ethanol (100 mM) treatment groups, cultured an additional 48 hr, and then half of them exposed to NMDA for 25 min. The NMDA was then removed and cells cultured in fresh media for an additional 24 hr to allow for excitotoxic delayed neuronal death. Cultures were then stained with antibodies to 5-hydroxytryptamine or tyrosine hydroxylase to identify serotonin and dopamine neurons, respectively. Cultures were analyzed for cell number and neuronal morphology. RESULTS: Ethanol treatment alone had no effect on biogenic amine cell number, soma area, number of neurites, or terminal segments, although the field area of dopamine neurons was decreased. Treatment with 30 microM NMDA had no effect on controls, but significantly decreased dopamine neurons in ethanol-treated cultures as well as reduced soma area, field area, number of neurites and number of terminal segments. Treatment with higher concentrations of NMDA reduced dopamine and serotonin neurons in both controls and ethanol-treated groups, and ethanol treatment significantly enhanced NMDA excitotoxic effects. Treatment with Brain Derived Neurotrophic Factor (BDNF) prevented ethanol sensitization to NMDA excitotoxicity. CONCLUSIONS: These studies suggest that ethanol treatment sensitizes biogenic amine neurons to excitotoxic insults. Ethanol sensitization of biogenic amine neurons to insults could contribute to the development of mental disease.

Animals↗
PubMedDate not supplied

Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence?

BACKGROUND: It has been suggested that normal concentrations of biogenic amines and 'histamine-releasing foods' may exacerbate symptoms in mastocytosis. The purpose of this study was to look for scientific evidence in the literature on diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastocytosis. METHODS: Medline (1966 to 2004), Cinahl (1982 to 2004) and the Cochraine Library were searched for double-blind placebo-controlled food challenge (DBPCFC) studies with biogenic amines and/or histamine-releasing foods in mastocytosis. RESULTS: No studies employing DBPCFC with dietary biogenic amines or histamine-releasing foods in mastocytosis were found. Only a few in vitro studies in other diseases, animal studies and studies in humans in which histamine-releasing agents were incubated directly with duodenal tissues were found. One case was reported of severe adverse reactions to alcohol in mastocytosis, objectified by an open challenge. CONCLUSION: Despite the widespread belief that biogenic amines and histamine-releasing foods may cause allergy-like, non-IgE-mediated symptoms in certain patients, the role of diets restricted in biogenic amines and histamine-releasing foods in the treatment of mastosytosis remains hypothetical but worthy of further investigation. There is some evidence for adverse reactions to alcohol in mastocytosis.

Animals↗
PubMed1991

The organic functional group in copper-containing amine oxidases. Resonance Raman spectra are consistent with the presence of topa quinone (6-hydroxydopa quinone) in the active site.

Resonance Raman spectroscopy has been used to probe the structure of the organic cofactor in copper-containing amine oxidases from bovine plasma, porcine kidney, pea seedlings, and the bacterium Arthrobacter P1. The enzymes were first derivatized with phenylhydrazine or p-nitrophenylhydrazine; resonance Raman spectra were obtained on the intact derivatized enzymes and on a derivatized active-site peptide isolated from bovine plasma amine oxidase. Spectra of the intact amine oxidase phenylhydrazones are practically identical, consistent with the enzymes examined containing a similar cofactor. Only minor frequency shifts and some intensity variations are detected between the resonance Raman spectra of intact bovine plasma amine oxidase and the isolated peptide. These spectral perturbations are attributable to differences in the micro-environment between the intact, folded protein and the isolated small peptide in aqueous solution. This rules out the possibility that a new structure is formed during the isolation of the derivatized active-site peptide. Importantly, the resonance Raman spectra of the phenylhydrazine and p-nitrophenylhydrazine derivatives of the bovine plasma amine oxidase peptide are identical to the spectra of the corresponding derivatives of topa quinone (6-hydroxydopa quinone). Hence these data provide strong, independent support for the recent identification of topa as the organic functional group in bovine plasma amine oxidase (Janes, S. M., Mu, D., Wemmer, D., Smith, A. J., Kaur, S., Maltby, D., Burlingame, A. L., and Klinman, J.P. (1990) Science 248, 981-987).

Amine Oxidase (Copper-Containing)↗
PubMed1989

Gas liquid chromatography of amines produced by the Enterobacteriaceae.

1. Gas liquid chromatography (GLC) was used to test the production of amines by 85 strains of Enterobacteriaceae. 2. The strains tested produced cadaverine, beta-phenylethylamine, putrescine, iso-amylamine, 2-methylbutylamine and iso-butylamine. 3. Although the overlap in amine production between obviously different genera and species limits the general applicability of this methodology in clinical microbiology, the results obtained demonstrate the possibility of differentiating Proteus rettgeri from other Proteus species, Escherichia coli from Proteus species and Salmonella species from Shigella species on the basis of their amine composition. 4. In general, members of the Enterobacteriaceae family produce qualitatively similar amine profiles, though differing quantitatively in the amounts of individual amines produced. GLC proved to be useful for separating amines and for providing tentative peak identification.

Amines↗
PubMed1986

Substrate specificity of the rabbit lung flavin-containing monooxygenase for amines: oxidation products of primary alkylamines.

Substrate activity of a flavin-containing monooxygenase isolated from rabbit lung microsomes has been examined with a number of primary, secondary, and tertiary amines. Of the secondary and tertiary amines tested, trifluoperazine, prochlorperazine, N, N-dimethyloctylamine, desmethylperazine, and N-methyloctylamine half-saturate the enzyme at concentrations less than 100 microM. Although the lung enzyme does not exhibit detectable substrate activity with primary arylamines, it catalyzes N-oxygenation of alkylamines to oximes. Studies on the mechanism for the oxidation of n-dodecylamine suggest that the amine is first oxidized to the hydroxylamine which is then further oxidized to the oxime. This interpretation is based on product identification, kinetic studies, and changes in the ratio of hydroxylamine to oxime formed as a function of initial substrate concentration. Kinetic constants calculated for the oxidation of n-dodecylamine and n-dodecylhydroxylamine indicate that the latter saturates the enzyme at a 100-fold lower concentration than that required for the parent amine, and the hydroxylamine is the dominant product only at saturating concentrations of the amine. The ratio of substrate-dependent NADPH and O2 consumption and product formation (hydroxylamine + 2 X oxime) is approximately 1.0:0.9:0.7. Although the reason for the less than stoichiometric yield of products is not known, uncoupling of the enzyme by primary amines does not appear to be a major factor since substrate-dependent increase in H2O2 formation is never more than 3% of substrate-dependent O2 consumption.

Amines↗
PubMed1987

Reductive trapping of substrate to bovine plasma amine oxidase.

Plasma amine oxidases catalyze the oxidative deamination of amines to aldehydes, followed by a 2e- reduction of O2 to H2O2. Pyrroloquinoline quinone (PQQ), previously believed to be restricted to prokaryotes, has recently been proposed to be the cofactor undergoing reduction in the first half-reaction of bovine plasma amine oxidase (Ameyama, M., Hayashi, U., Matsushita, K., Shinagawa, E., and Adachi, O. (1984) Agric. Biol. Chem. 48, 561-565; Lobenstein-Verbeek, C. L., Jongejan, J. A., Frank, J., and Duine, J. A. (1984) FEBS Lett. 170, 305-309). This result is unexpected, since model studies with PQQ implicate Schiff's base formation between a reactive carbonyl and substrates, whereas experiments with bovine plasma amine oxidase have failed to provide evidence for a carbonyl cofactor. We have, therefore, re-examined putative adducts between substrate and enzyme-bound cofactor, employing a combination of [14C]benzylamine and [3H]NaCNBH3. The use of the relatively weak reductant, NaCNBH3, affords Schiff's base specificity and permits the study of enzyme below pH 7.0. As we show, enzyme can only be inactivated by NaCNBH3 in the presence of substrate, leading to the incorporation of 1 mol of [14C]benzylamine/mol of enzyme subunit at complete inactivation. By contrast, we are unable to detect any labeling with [3H]NaCNBH3, analogous to an earlier study with [3H]NaCNBH4 (Suva, R. H., and Abeles, R. H. (1978) Biochemistry 17, 3538-3545). We conclude, first, that our inability to obtain adducts containing both carbon 14 and tritium rules out the reductive trapping either of amine substrate with pyridoxal phosphate or of aldehyde product with a lysyl side chain and, second, that the observed pattern of labeling is fully consistent with the presence of PQQ at the active site of bovine plasma amine oxidase.

Amine Oxidase (Copper-Containing)↗
PubMed1982

Amines in soil as possible precursors of N-nitroso compounds.

Volatile nitrogen bases in soil have been analysed by gas chromatography. Two samples of soils taken from different regions have been investigated. The first sample was loam. The second was a mixed sample with a predominance of chernozem. At least 48 amines have been found in the samples and 34 of them have been identified. Among the compounds identified are primary, secondary and tertiary amines and heterocyclic bases. The most numerous group is that of the secondary amines (14 compounds), which can be directly nitrosated to give carcinogenic N-nitrosamines. In the chernozem soil, the qualitative amine analysis is practically identical to that of the loam, but the total amount of amines is approximately 10 times higher. For the first time, a wide variety of amines capable of undergoing nitrosation has been found in soils not cultivated by man.

Amines↗
PubMed1994

[N-acetylation polymorphism versus differentiation of organic susceptibility to carcinogenic effect of homo- and heterocyclic aromatic amines].

Smoking and consumption of fried and smoked meat play, besides occupational exposure, a significant role in the etiology of neoplasm induced by chemical carcinogens. Homo- and heterocyclic aromatic amines which are present in tobacco smoke and generate during meat processing are of special concern. Homocyclic aromatic amines are mainly responsible for inducing neoplasm of bladder while heterocyclic amines induce neoplasm of colon. Acetyltransferase is essential in transformation of cells in both groups of aromatic amines. The studies carried out so far indicate that persons displaying low cellular activity of acetyltransferase, so called slow acetylators, are more susceptible to neoplasm of bladder under condition of exposure than those displaying high acetyltransferase activity (fast acetylators). However, under exposure to heterocyclic aromatic amines fast acetylators are more susceptible to neoplasm of colon than slow acetylators. The distinction between fast and slow acetylators as for as susceptibility to neoplasms of bladder and colon is concerned results from different nature of metabolism homo- and heterocyclic aromatic amines undergo in the liver.

Acetyltransferases↗
PubMed1993

Study of the complex formation between amine local anesthetics and uncouplers of oxidative phosphorylation carbonyl cyanide phenylhydrazones.

Spectroscopic evidence is presented which indicates that the anionic uncoupler carbonyl cyanide-4-nitro-2-chloro-phenylhydrazone and the amine local anesthetics form a complex in aqueous solution. The complex formation studies were carried out for several pharmacologically important tertiary amines and some primary amines. Their relative potencies to form a complex with uncoupler have followed the order: procaine < trimecaine < tetracaine < dibucaine < dodecylamine < dicyclohexylamine < hexadecylamine. As to the more lipophilic nature of the complex the emphasized penetration into octanol and reinforced retention into mitochondria was observed. The higher ability of the complex to colapse the mitochondrial membrane potential confirms this fact. The effective concentration of amine local anesthetics to form a complex was correlated with their physicochemical properties namely lipophilicity and acidobasicity. The highest effectivities for complex formation is shown by the most lipophilic and the most ionized molecules of amines. Present results point to the importance of considering the role of amine anesthetic-uncoupler complex in interpreting physiological or ion transport data in which these substances have been used together.

Amines↗
PubMed1998

Glucuronidation of amine substrates by purified and expressed UDP-glucuronosyltransferase proteins.

Conjugation of many primary, secondary, and tertiary amine-containing xenobiotics with glucuronic acid can result in the formation of N-glucuronide metabolites. For carcinogenic arylamines and their N-hydroxylated metabolites, N-glucuronidation can result in the formation of either inactive metabolites or labile conjugates, which can be transported to their target tissue (urinary bladder) where they may be converted to reactive metabolites. Drugs with primary amine (e.g. dapsone) or secondary amine moieties (e.g. sulfadimethoxine and clozapine) can also be metabolized to N-glucuronides. The metabolism of a number of tertiary amine-containing pharmacological agents to quaternary ammonium-linked glucuronides represents a unique and important metabolic pathway for these compounds that is highly species-dependent. This review summarizes our present knowledge of the uridine diphosphate (UDP)-glucuronosyltransferase enzymes involved in catalyzing N-glucuronide formation. Of the more than 30 UDP-glucuronosyltransferases that have been purified or cloned and expressed, many catalyze N-glucuronide formation for primary and secondary amine substrates. In contrast, only human UDP-glucuronosyltransferases 1A3 and 1A4 have been shown to catalyze quaternary ammonium-linked glucuronide formation for aliphatic tertiary amines. The structure of the UGT1 gene complex is highly conserved across species, and it appears that a mutation in the first exon encoding UDP-glucuronosyltransferase 1A4, resulting in a pseudo-gene, may explain the inability of some species to form quaternary ammonium-linked glucuronides.

Amines↗
PubMed1999

Non-amine dopamine transporter probe [(3)H]tropoxene distributes to dopamine-rich regions of monkey brain.

Drug development in psychopharmacology has adhered to the unwritten precept that compounds targeting monoamine transporters must contain an amine nitrogen in the molecular structure. A series of non-amine-bearing aryloxatropanes that are potent inhibitors of the dopamine transporter (DAT) challenged this precept. In the present study, we investigated the brain distribution of a selective, high-affinity DAT non-amine, [(3)H]tropoxene (2-carbomethoxy-3, 4dichloro-3-aryl-8-oxabicyclo[3.2.1] octene), which binds to the DAT in monkey striatum. The autoradiographic distribution of [(3)H]tropoxene was conducted in tissue sections of rhesus (Macaca mulatta) monkey brain. Highest accumulation of the radioligand was detected in the putamen and caudate nucleus, with significant levels also observed in the nucleus accumbens and substantia nigra. Moderate to low levels of [(3)H]tropoxene binding were noted in the hypothalamus, amygdala, ventral tegmental area, and thalamus. The distribution of [(3)H]tropoxene was restricted to brain regions previously identified as expressing DAT, and the relative densities of [(3)H]tropoxene binding sites in various brain regions corresponded to those observed with other selective monoamine radioligands for the DAT. This is the first report to demonstrate that transporter-selective compounds that bear no amine nitrogen in their structure bind selectively to brain regions rich in the transporter. The results support our conclusion that an amine nitrogen is not necessary for compounds to bind to monoamine transporters and distribute in brain according to the known distribution of transporters. The findings provide further incentives to investigate the pharmacological potential of transport inhibitors lacking an amine nitrogen in the molecular structure.

Animals↗
PubMed1998

Assessing the predictiveness of the Syrian hamster embryo cell transformation assay for determining the rodent carcinogenic potential of single ring aromatic/nitroaromatic amine compounds.

The pH 6.7 Syrian hamster embryo (SHE) cell transformation assay was used to test the morphological transformation potential of 5 rodent carcinogenic single ring aromatic/nitroaromatic amine compounds: 2-amino-4-nitrotoluene, 2,4-diaminotoluene, 2,4-dinitrotoluene, o-anisidine hydrochloride, and o-toluidine; and 5 noncarcinogenic single ring aromatic/nitroaromatic amine compounds: 2,6-diaminotoluene, 2,4-dimethoxyaniline hydrochloride, 4-nitro-o-phenylenediamine, p-phenylenediamine dihydrochloride, and HC Blue No. 2. All 5 rodent carcinogens produced significant morphological transformation in a dose-responsive manner. None of the 5 noncarcinogens yielded significant transformation at any of the doses tested. Therefore, the concordance between the pH 6.7 SHE cell transformation assay and rodent carcinogenicity for these 10 single ring aromatic/nitroaromatic amine compounds is 100%. In contrast, the concordance between the standard SHE cell transformation assay and rodent carcinogenicity for 13 single ring aromatic/nitroaromatic amine compounds was 62%. For 5 aromatic/nitroaromatic amine compounds which were tested in both standard and pH 6.7 SHE cell transformation assays (i.e., a subset of the above two databases), the concordance between the standard SHE cell transformation assay and the rodent bioassay was 40%, while the concordance between the pH 6.7 SHE cell transformation assay and the rodent bioassay was 100%. This relatively high concordance between the pH 6.7 SHE cell transformation assay and rodent bioassay results demonstrates the utility of the pH 6.7 SHE cell transformation assay for predicting the rodent carcinogenic potential of single ring aromatic/nitroaromatic amine compounds.

Aniline Compounds↗
PubMed1987

Effects of deuterium substitution on the chronotropic responses to some sympathomimetic amines in the isolated rat atria.

In spontaneously beating rat atria the potencies for the chronotropic effects of the following deuterated phenylethylamine derivatives were higher than the potencies of the corresponding non-substituted (protio-) amines: alpha,alpha,d2-beta-phenylethylamine; alpha,alpha,beta,beta-d4-p-tyramine; alpha,alpha,beta,beta-d4-m-tyramine; alpha,alpha,beta-d3-p-octopamine. In contrast, alpha,alpha,beta-d3-noradrenaline and alpha,alpha,beta-d3-m-octopamine were equipotent with the corresponding protio-amines. Experiments performed in atria depleted of endogenous noradrenaline by pretreatment with reserpine and in atria exposed to the monoamine oxidase (MAO) inhibitor pargyline indicated: a. p-octopamine had both direct and indirect effects, but the chronotropic responses to p-octopamine in tissues with normal MAO activity depended mostly on the direct action of the amine; deuterium substitution enhanced the indirect component of action of p-octopamine; b. m-octopamine possessed considerable indirect effects while d3-m-octopamine behaved as an amine of direct action. The substitution of deuterium for hydrogens in the alpha-carbon of the alkyl-side chain of phenylethylamines decreases the rate of deamination by MAO. Therefore, the results obtained with all the amines, except for m-octopamine and alpha, alpha,p-d3-m-octopamine, could be interpreted in terms of the direct, indirect or mixed action of those compounds and/or of the influence that MAO activity has on the chronotropic responses to these amines. The results obtained with protio- and deuterio-m-octopamine suggested that deuterium substitution, either at the alpha- or the beta-carbon, can alter some other mechanisms in addition to the enzymatic deamination.

Animals↗
PubMed1981

Toxic and teratogenic effects of selected aromatic amines on embryos of the amphibian Xenopus laevis.

Evaluations of the toxic and teratogenic effects of four aromatic amines, acridine, aniline, pyridine, and quinoline, have been made on amphibian (Xenopus laevis) embryos. For toxicity testing, the embryos were divided into three groups according to stage of development: Group I were mid-blastulae, Group II were tailbud embryos, and Group III were swimming larvae. Of the amines tested, acridine and quinoline were the most toxic, followed by aniline and pyridine. Ninety six hr LC50 values for acridine, quinoline, aniline, and pyridine were 4.5, 95, 150, and 1090 mg/L, respectively, for Group III larvae. Except for acridine, where embryos in all three groups were about equally affected, those in Group II were less sensitive to the other amines than those in Groups I and III. Group I embryos were exposed to all four amines to determine their teratogenicity. The amines were ranked in order to decreasing teratogenicity: acridine, quinoline, aniline, and pyridine having 96-hr EC50 values of 2.4, 29, 370, and 1200 mg/L, respectively. Electron microscopic examination of Group III larvae exposed to these amines reveals pathology of the spinal cord and musculature. This damage was correlated with immobility of the larvae. The uptake of acridine was followed in larvae (Group III) exposed to 5 mg/L and was found to reach a maximum level of about 85 mg/g wet weight in about one hr. Depuration kinetics were characterized by a rapid loss of 70% of the total acridine within 45 min. Acridine was undetectable after two hr. These data suggest that acridine, aniline, and quinoline have toxic and teratogenic effects at sufficiently low concentrations as to make them potential environmental hazards.

Acridines↗
PubMed1988

Fibroblasts maintain a complete endocytic pathway in the presence of lysosomotropic amines.

We have investigated the effects of the lysosomotropic amines, ammonium chloride and chloroquine, on the delivery of fluid-phase pinocytic tracers to lysosomes in Chinese hamster ovary (CHO) cells. In preliminary experiments, 15 mM ammonium chloride and 0.1 mM chloroquine were found to be sufficient to give maximal protection of endocytosed material from digestion in a lysosome. In the presence of either amine at these concentrations, the generation time of CHO cells was depressed by less than 30% even though selective depletion of lysosomal hydrolases was observed. For cells treated with either amine for 1 or 6 days the amount of horseradish peroxidase (HRP) internalized in a 1-h pulse was approximately 50-70% of that of control. By cell fractionation, cells treated with amine for 2 or 6 days were found to accumulate fluorescein-dextran or HRP in lysosomes. HRP accumulation in lysosomes in amine-treated cells was also observed by electron microscopy. Little exocytosis of lysosomal HRP into the media was observed under any condition. We conclude that in long-term amine-treated CHO cells endocytic vesicle traffic is maintained.

Ammonium Chloride↗
PubMed1980

Primary amines inhibit recycling of alpha 2M receptors in fibroblasts.

Receptor-mediated endocytosis of alpha 2M-protease complexes by normal human skin fibroblasts in culture was inhibited by the primary amines, methylamine and mono-dansylcadaverine. The latter was effective at a concentration two orders of magnitude lower than methylamine. Several observations indicated an intracellular mode of action of these amines, excluding interference with binding of alpha 2M to the receptor. Inhibition of endocytosis was dissociated from lysosomotropic effects of these amines by kinetic analysis of endocytosis. As opposed to chloroquine and alkaline incubation conditions (pH 8.0), the amines reduced the maximal rate of endocytosis considerably, indicating a reduction in number of available receptors. This was confirmed by measuring binding at 4 degrees C. Continuous recycling of receptors is indicated by the absence of down-regulation of number of receptors under conditions saturating for endocytosis of alpha 2M complexes. We postulate that the primary amines, methylamine and mono-dansylcadaverine, interfere with the recycling of alpha 2M receptors, while the chemical nature of the amines and the conditions under which inhibition becomes apparent point to the involvement of transglutaminase in this recycling.

Cadaverine↗
PubMed1979

Interactions of pharmacological agents which alter biogenic amine metabolism and depression--an analysis of contributing factors within a primate model of depression.

The observation that the biogenic amine depleting agent, reserpine, could induce severe depression in a small proportion of the patients treated with it has proved to be seminal finding in what is now a much larger field of research relating the function brain biogenic amine systems to emotions and behavior. A review of the human reserpine literature suggests, however, that factors other than pharmacologically produced alterations in brain biogenic amine metabolism must have been critical determinants of the eventual mood alterations observed in conjunction with reserpine treatment. While some of these factors, such as previous history of depression, ongoing psychosocial and environmental stress, can be intuitively identified, there are practical as well as ethical problems involved in actually testing the relative contribution of these factors in precipitating human depression and thereby determining their importance in a quantitative fashion. In the present paper we have attempted to examine, in a nonhuman primate model of depression, the degree to which factors such as prior rearing condition, repeated peer separation, and housing environment can intact with the behavioral effects produced by biogenic amine depleting agents. Major emphasis will be placed on studies utilizing alpha-methyl-para-tyrosine, an inhibitor of tyrosine hydroxylase, to ostensively reduce levels of the catecholamine neurotransmitters norepinephrine and dopamine. The results of these studies provide quantitative estimates, in terms of dose-effect relationships, of the degree to which a number of factors can combine to produce despair-like behavior in rhesus monkeys. These data may be of practical importance in evaluating the contribution of similar factors to the precipitation of human depression. Analysis of some of the existing literature relating alterations in behavior to changes in biogenic amine metabolism in animals suggests that there are important differences between rodent and primate species. These differences, when fully established, may indicate that additional research examining the mechanisms whereby modest alterations in biogenic amine metabolism can interact with environmental and social stress is needed.

Animals↗
PubMed1989

Uptake of heterocyclic amines, Trp-P-1 and Trp-P-2, into clonal rat pheochromocytoma PC12h cells by dopamine uptake system.

Heterocyclic amines, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), are known to be produced in food by cooking and are carcinogenic. These amines were found to be accumulated in clonal rat pheochromocytoma PC12h cells and to reduce enzyme activity related to catecholamine synthesis. The mechanism of uptake of these heterocyclic amines into PC12h cells was studied. The uptake was dependent on the incubation time, the amount of the cells, and the concentrations of Trp-P-1 and Trp-P-2 in the incubation mixture. The uptake of these amines was saturable with their concentrations, and the uptake velocity followed the Michaelis-Menten equation, indicating that the uptake was mediated by a transporting protein. The uptake was inhibited by dopamine and serotonin, but not by noradrenaline. Involvement of the dopamine uptake system in uptake of the heterocyclic amines was further indicated by the fact that nomifensine and mazindol, specific inhibitors of dopamine uptake, reduced the uptake, but sulpiride, an antagonist of D2 receptor, did not. The significance of the uptake of the carcinogenic heterocyclic amines was discussed in relation to their possible neurotoxicity in the human brain.

Adrenal Gland Neoplasms↗