Gene/Protein Disease Symptom Drug Enzyme Compound
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The specific granules found in the atrial cardiac muscle cells of the normal rat were studied. The ultrastructural appearance of these granules demonstrated a fixative-dependent lability. Fixation with cacodylate buffered aldehydes yields three types of granules. However, fixation with phosphate buffered aldehydes or primary fixation with OsO4 yields granules of uniform appearance. The granules are found predominantly in the perinuclear zone; 78% of the granules are within ten linear micrometers of the center of the nucleus. Two independent methods of measurement demonstrate spherical diameters of these granules of 0.30 micron and 0.37 micron respectively. The granules are found in greater concentration at one pole of the nucleus than at the other. On the high density side there are 4.07 granules/micrometers3 which occupy 5.8% of the cytoplasmic volume. On the low density side there are 2.15 granules/micrometers3 which occupy 3.0% of the cytoplasmic volume. The granules at both poles are the same size. Atrial walls were incubated in a modified Tyrode's solution. One hour of incubation caused no change in the atrial granules. Addition of norepinephrine or L-Dopa resulted in the appearance of more granules but the size of the granules remained the same. Incubation with reserpine had no effect upon the atrial granules. Apparently the atrial myocardial cell is stimulated by exogenous catecholamine to synthesize more atrial granules which themselves do not appear to contain catecholamines.
Anat Rec 1979 Aug
PMID:Specific granules of the rat atrial muscle cell. 11 80

The general body epidermis of the rhesus monkey (Macaca mulatta) contains no discernible melanocytes, but after repeated ultraviolet irradiation DOPA-positive melanocytes appear and increase numerically up to 30 exposures. With continued irradiation, however, the number again declines. Experiments to determine how melanogenic activity, assayed by the incorporation of labeled DOPA or tyrosine, is related to DOPA positivity indicated that biochemical activity corresponded to the histochemical pattern. Ultrastructural studies demonstrated that after the exposure to ultraviolet light a pool of indeterminate cells in the skin of rhesus monkeys developed into malanocytes. The melanosomes formed by these cells, however, differed from the eumelanin melanosomes described in other species; they had no internal filamentous matrix with periodicity but appeared similar to phaeomelanin melanosomes. Long term ultraviolet light irradiation may damage keratinocytes and render them incapable of phagocytizing melanosomes.
Anat Rec 1976 Apr
PMID:The use of ultraviolet light to induce melanogenesis in the epidermis of the rhesus monkey: an ultrastructural and biochemical study. 81 26

Apomorphine, N-nor-N-propyl-apomorphine, dopamine, L-DOPA, 6-hydroxydopamine and adrenaline were evaluated for genotoxicity using the Ames test and DNA repair-deficient and DNA repair-proficient Bacillus subtilis strains (rec assay, H17/M45; HLL3g/HJ-15). In the absence of an S9 liver homogenate, apomorphine induced frame-shift mutations in Salmonella typhimurium, mainly in strain TA1537; no indication of DNA-damaging effects in B. subtilis was observed. N-Nor-N-propyl-apomorphine was tested using strain TA1537 only and found to be mutagenic. Dopamine, L-DOPA, 6-hydroxydopamine and adrenaline were non-mutagenic when tested without S9, whereas they were all more toxic for DNA repair-deficient than for DNA repair-proficient B. subtilis strains, indicating a DNA-damaging potential. In a second set of experiments the mode of action of apomorphine and the relevance of the positive Ames test data were investigated. Glutathione in physiological concentrations reduced the mutagenic effect of apomorphine in a dose-dependent way, both in the presence and the absence of S9. S9 also reduced the mutagenicity of apomorphine. By comparing the effects of a complete S9 mix with those of a preparation without glucose-6-phosphate and NADP, it became clear that S9 also had an activating effect, overshadowed under standard conditions by its deactivating activity. Apomorphine was not mutagenic under anaerobic conditions. Superoxide dismutase and catalase reduced the mutagenic effect of apomorphine. All test conditions which reduced the mutagenic effect also inhibited the dark discoloration of the tester plates, indicating a retardation of apomorphine oxidation. It can, therefore, be concluded that oxidation of apomorphine leads to mutagenic products which induce frame-shift mutations in Salmonella typhimurium. This oxidation was prevented both by glutathione in concentrations well below physiological levels and/or by catalase and superoxide dismutase. Under these conditions, apomorphine was non-mutagenic in therapeutic concentrations as well as at higher dose levels. The possibility of genotoxic side effects occurring in patients treated with apomorphine as an emetic drug is therefore considered to be very unlikely.
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PMID:Genotoxicity of apomorphine and various catecholamines in the Salmonella mutagenicity test (Ames test) and in tests for primary DNA damage using DNA repair-deficient B. subtilis strains (rec assay). 643 Dec 80

We have investigated morphologic and histochemical characteristics of serotonin-containing epithelial cells in tracheas from adult rabbits, using the Falck-Hillarp freeze-dried formaldehyde vapor technique. An intracellular formaldehyde-induced fluorescent substance was identified as serotonin by microspectrofluorometric techniques. Fluorescence microscopy and subsequent histochemical staining of the same sections demonstrated that serotonin-containing cells were argentaffin-, argyrophil-, and ferric ferricyanide-positive. The serotonin-containing epithelial cells were more numerous in ventral than in dorsal aspects of trachea. The number of detectable fluorescent cells was reduced after reserpine administration but was not affected by injecting the amine precursor L-dihydroxyphenylalanine (L-DOPA). The emission peak of the fluorophore was not significantly shifted after L-DOPA injections. The cells may regulate tracheobronchial-pulmonary function by releasing serotonin or other as yet unidentified biologically active substances.
Anat Rec 1981 Jan
PMID:Morphology, histochemistry, and distribution of serotonin-containing cells in tracheal epithelium of adult rabbit. 722 99

The effects of noradrenaline (NA), L-3, 4-dihydroxyphenylalanine (L-DOPA), 5-hydroxydopamine (5-OHDA), 6-hydroxydopamine (6-OHDA), and reserpine (RES) on the uptake, accumulation, and release of amines in catecholamine-containing specific endothelial granules (SEG) of carp cerebral veins and their mode of formation were examined by fluorescence histochemistry and electron microscopy. The intramuscular injection of NA (4 mg/kg) or L-DOPA (200 mg/kg) resulted in an increase in both the fluorescence and electron density of SEG. After the administration of false neurotransmitters. 5-OHDA (190 mg/kg) or 6-OHDA (200 mg/kg), the venous endothelial fluorescence almost completely disappeared but the SEG electron density increased. Following the injection of RES (15 mg/kg), the fluorescence intensity and SEG electron density showed no sign of decrease, as was expected, but in fact increased. It is suggested that the SEG are able to take up and accumulate exogeneous amines and that these mechanisms are RES-resistant. The electron density of SEG increased in proportion to the amount of amines in the SEG. The swelling and fragmentation of rough endoplasmic reticulum cisternae and the accumulation of dense material within the cisternae suggests the possible participation of these organelles in SEG formation.
Anat Rec 1980 Nov
PMID:Further studies on catecholamine-containing specific endothelial granules in carp cerebral veins. A fluorescence histochemical and electron microscopy study. 745 35

The flavoprotein D-amino acid oxidase (DAO) degrades the gliotransmitter D-Ser, a potent activator of N-methyl-D-aspartate-type glutamate receptors. A body of evidence suggests that DAO, together with its activator, G72 protein, may play a key role in the pathophysiology of schizophrenia. It has also been suggested that 3,4-dihydroxy-D-phenylalanine (D-DOPA), the stereoisomer of 3,4-dihydroxy-L-phenylalanine (L-DOPA), is oxidized by DAO and converted to dopamine via an alternative biosynthetic pathway. We determined the crystal structures of human DAO in complex with the reaction products of two clinically important substrates, D-Ser and D-DOPA. Kinetic data show that the maximum velocity is much greater for D-DOPA than that for D-Ser, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, biochemical characterization of human DAO indicates that it binds FAD more weakly than does porcine D-amino acid oxidase (pDAO) and exists as a stable homodimer, even in the apoprotein form. Determination of the structures of human DAO in various states reveals that, in contrast to pDAO, the hydrophobic-Val-Ala-Ala-Gly-Leu (VAAGL) stretch (residues 47-51, structurally ambivalent peptide) located at the si-face of the flavin ring assumes a uniquely stable conformation, which provides a structural basis for the unique kinetic features of human DAO.
Chem Rec 2007
PMID:Human D-amino acid oxidase: an update and review. 1792 43

(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for aromatic amino acid hydroxylases, such as phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), tryptophan hydroxylase, and nitric oxide synthase, which catalyze physiologically important reactions in mammals. The biosynthesis and metabolism of BH4 is usually studied mostly in the liver and only slightly in the brain, as the BH4 level in the liver is relatively high because BH4 is required for the reaction of PAH. We found that GTP (guanosine triphosphate) cyclohydrolase I, an enzyme for the biosynthesis of BH4, is a causative gene for DOPA (3,4-dihydroxyphenylalanine)-responsive dystonia (also called Segawa's disease), and that partial deficiency of BH4 leads to the dysfunction of the nigrostriatal dopaminergic neurons without hyperphenylalaninemia. We analyzed BH4-deficient mice that were produced by disruption of a BH4-synthesizing gene by a gene-knockout technique. We found that the protein amount of TH was highly dependent on the amount of BH4, especially in nerve terminals. Our research suggests that BH4 metabolism in the brain should be different from that in the liver, and that altered metabolism of BH4 should lead to neuropsychiatric disorders including Parkinson's disease.
Chem Rec 2008
PMID:Metabolism of tetrahydrobiopterin: its relevance in monoaminergic neurons and neurological disorders. 1910 67