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Query: UNIPROT:P06889 (Mol)
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The ability of 3,3',4,4'-tetrachlorobiphenyl to stimulate bilirubin degradation by liver microsomes from rats treated with a polycyclic aromatic hydrocarbon-type inducer has been confirmed and extended to another planar biphenyl, 3,3',4,4',5,5'-hexachlorobiphenyl. The following evidence indicates the involvement of an inducible cytochrome P450 isoenzyme in this reaction, with a role, specifically, for cytochrome P450IA1. (a) The biphenyl-dependent bilirubin degradation and 7-ethoxyresorufin O-deethylase (EROD) activity were both markedly inhibited by a monoclonal antibody raised against cytochrome P450IA1; the two dose-inhibition curves were essentially superimposable, with maximum inhibition observed for both activities at a ratio of antibody to total cytochrome P450 of about 1. (b) Treatment of rats with 3-methylcholanthrene increased both EROD activity and biphenyl-dependent bilirubin degradation not only in the liver (where both cytochromes P450IA1 and P450IA2 are inducible) but also in the kidney (where only induction of cytochrome P450IA1 has been reported), with similar ratios of the two enzymatic activities in both tissues. (c) With carbon tetrachloride and 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,4-dimethyl pyridine as selective suicide substrates of members of the cytochrome P450IA subfamily, the biphenyl-dependent degradation of bilirubin showed a good correlation with cytochrome P450IA1, determined both as EROD activity and as an immunoreactive band on immunoblotting. These findings implicate cytochrome P450IA1 in the alternative pathway of bilirubin disposal, which can be stimulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin in Gunn rats, and also help substantiate the hypothesis that interaction of a polyhalogenated aromatic compound with the induced cytochrome may initiate an oxidative mechanism leading to oxidation of target molecules in the cell, one of which is bilirubin.
Mol Pharmacol 1991 Nov
PMID:Inducible bilirubin-degrading system of rat liver microsomes: role of cytochrome P450IA1. 194 39

The major protein-rich foods, particularly muscle meats, contain part-per-billion quantities of potent mutagens formed by frying or broiling to a well-done state. Related mutagens are formed by pyrolysis of amino acids or proteins and in heated model systems. The thermic mutagens so far identified are heterocyclic aromatic amines of aminoimidazo-azaarene (AIA) and aminocarboline classes. The chemicals require activation by enzymes to form metabolites reactive with nucleic acids. These thermic mutagens, and numerous synthetic congeners, exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. However, structural variations are nominal within the two classes. Structural parameters that appeared relevant to determining potency were selected for 38 AIAs and 23 amino-carbolines. For the AIA class these were: the number of fused rings, the number of heteroatoms in Rings 2 and 3, methyl substitution on imidazo ring nitrogen atoms, and methyl substitution on ring carbon atoms. For the amino-carboline class the structural parameters were: the position of the pyridine-type nitrogen atom in Ring 1, the substitution position of the exocyclic amino group on Ring 1, and methyl substitution on ring carbon atoms. These structural parameters may influence mutagenic potency in the following ways. 1) Electronic or steric effects may determine the reactivity and stability of the ultimate mutagenic metabolite. Optimal balance of reactivity and lifetime of this transient intermediate may be required for access to and reaction with nuclear DNA to cause mutations. 2) Substitution on the rings may block detoxication reactions. The structural parameters identified should prove useful in predicting the mutagenicity of untested compounds of these types.
Environ Mol Mutagen 1991
PMID:Quantitative structure-activity relationships of heterocyclic amine mutagens formed during the cooking of food. 199 58

A quantitative structure-activity relationship study of a set of antiulcer compounds has been performed using the computer-automated structure evaluation methodology. Computer-automated structure evaluation identified cyanomethyl and hydroxymethyl functionalities, substituted in the 3-position of imidazo[1,2-a]pyridine and -Pyrazine, as descriptors relevant to antisecretory activity. The phenoxy group at the 8-position and the methyl group at the 2-position were shown to be sterically involved in the activity. A parabolic relationship was observed between the antisecretory activity and the logarithm of the partition coefficient of the compounds. Thus, hydrophobicity is found to be a necessary criterion for the inhibition of acid secretion. An attempt has been made to provide a rationale for designing a more potent antiulcer agent in this series of congeneric compounds.
Mol Pharmacol 1990 Jun
PMID:Computer-automated structure evaluation of gastric antiulcer compounds: study of cytoprotective and antisecretory imidazo[1,2-a]pyridines and -pyrazines. 235 7

Ca2+ influx through voltage sensitive Ca2+ channels produces a rise in intracellular-free Ca2+, [Ca2+]i, that serves as a trigger for the release of neurotransmitters. We measured [Ca2+]i in primary cultures of superior cervical ganglion (SCG) neurons of the rat using 2-(6-(bis(carboxymethyl)amino)-5-methylphenoxy)ethoxy-2-benzofuranyl)5- oxazole carboxylic acid-based microfluorimetry. Recordings were obtained from either single or small bundles of neuronal processes and compared with recordings from single neuronal cell bodies. Depolarization with 50 mM K+ produced a rapid increase in [Ca2+]i consisting of both transient and sustained components. This response pattern was seen in recordings from both the soma and processes of SCG neurons. The entire response could be reversibly blocked by 30 microM La3+. Nitrendipine, 1 microM, inhibited the response by 52 +/- 7% and 49 +/- 7% in the soma and processes, respectively. The dihydropyridine (DHP) agonist 1,4-dihydro-2,-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine- 5-carboxylic acid methyl ester enhanced depolarization-induced increases in [Ca2+]i in both regions of the neuron. The transient component of the response was greatly reduced by predepolarization, and the remaining sustained component was inhibited 77 +/- 7% by nitrendipine (1 microM). These data demonstrate that both DHP-sensitive and -insensitive Ca2+ channels are present in processes as well as cell bodies of SCG neurons. The importance of these findings is discussed in relation to the insensitivity of neurotransmitter release from sympathetic neurons to DHP antagonists.
Mol Pharmacol 1987 Nov
PMID:Distribution of multiple types of Ca2+ channels in rat sympathetic neurons in vitro. 244 12

Addition of GnRH to pituitary gonadotrophs preloaded with Quin 2 resulted in a rapid (approximately 8 s) mobilization of an ionomycin-sensitive intracellular Ca2+ pool. A second component of Ca2+ entry via voltage dependent channels contributed about 45% of the peak cytosolic free Ca2+ concentration ([Ca2+]i). Thereafter, influx of Ca2+ via voltage-sensitive and -insensitive channels is responsible for maintenance of elevated [Ca2+]i during the second phase of GnRH action. Addition of inositol 1,4,5-trisphosphate (IP3) to permeabilized pituitary cells resulted in a Ca2+ transient, released from a nonmitochondrial pool, which maintained ambient free Ca2+ concentration around 170 nM in an ATP-dependent mechanism. Successive stimulations of the cells with IP3 produced an attenuated response. Elevation of the gonadotroph [Ca2+]i by ionomycin, to levels equivalent to that induced by GnRH, resulted in LH release amounting to only 45% of the response to the neurohormone. Activation of the voltage-dependent Ca2+ channels by the dihydropyridine Ca2+-agonist [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine- 5-carboxylate (BAYK8644)] stimulated LH release, 36% of the GnRH (100 nM) response being reached by 10(-8) M of the drug, both [Ca2+]i elevation and GnRH-induced LH release were inhibited similarly (40-50%) by the dihydropyridine Ca2+-antagonist nifedipine. The results indicate that peak [Ca2+]i induced by GnRH in pituitary gonadotrophs is derived mainly from ionomycin-sensitive cellular stores most likely via IP3 formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1988 Jun
PMID:Gonadotropin-releasing hormone-induced rise in cytosolic free Ca2+ levels: mobilization of cellular and extracellular Ca2+ pools and relationship to gonadotropin secretion. 245 25

The evolution of genetic material can be divided into at least three major phases: first, genomes of "nucleic acid-like" molecules; secondly, genomes of RNA; and finally, double-stranded DNA genomes such as those present in all contemporary cells. Using properties of nucleic acid molecules, we attempt to explain the evolutionary transition from RNA alone as a cellular informational macromolecule prior to the evolution of cell systems based on double-stranded DNA. The idea that ribonucleic acid-based cellular genomes preceded DNA is based on the following: (1) protein synthesis can occur in the absence of DNA but not of RNA; (2) RNA molecules have some catalytic properties; (3) the ubiquity of purine and pyridine nucleotide coenzymes as well as other similar ribonucleotide cofactors in metabolic pathways; and (4) the fact that the biosynthesis of deoxyribonucleotides always proceeds via the enzymatic reduction of ribonucleotides. The "RNA prior to DNA" hypothesis can be further developed by understanding the selective pressures that led to the biosynthesis of deoxyribose, thymine, and proofreading DNA polymerases. Taken together these observations suggest to us that DNA was selected as an informational molecule in cells to stabilize earlier RNA-protein replicating systems.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1988
PMID:The evolutionary transition from RNA to DNA in early cells. 246 98

Hypoxia and ischemia are potent stimuli to vascular growth. The mechanisms by which vascular growth is induced are unknown. During ischemia, such as that which occurs in the heart, purine and pyridine nucleotides are degraded and their metabolites accumulate. At least two of these metabolites, adenosine and nicotinamide, have previously been demonstrated to induce vascular growth. The goal of this study was to determine whether other purine and pyridine metabolites have the potential to stimulate angiogenesis in vivo, to determine the relative angiogenic potency of these metabolites, and to determine if their angiogenic effects is mediated through a direct effect on endothelial cell proliferation. Purine metabolites (adenosine, inosine, hypoxanthine, xanthine, guanosine, uric acid), the pyridine metabolite nicotinamide, and chemical derivatives of nicotinamide, were tested at various concentrations for their ability to stimulate angiogenesis in the chick choriollantoic membrane assay. Although none of the purine metabolites were effective in promoting the angiogenic response, nicotinamide as well as several derivatives of nicotinamide induced an angiogenic response in a dose-dependent manner. Nicotinamide was then evaluated to determine if its angiogenic effect is a result of a direct effect on capillary endothelial cell proliferation. In concentrations of 100 microM to 1 mM nicotinamide was not demonstrated to be mitogenic for bovine capillary endothelial cells. These results demonstrate that pyridine nucleotides are indirect angiogenic agents that do not exert a primary effect on endothelial cell proliferation. The results of this study suggest that increases in vascular growth induced by ischemia and hypoxia might be mediated, at least in part, by pyridine metabolites released from ischemic tissues.
J Mol Cell Cardiol 1989 Apr
PMID:Angiogenic potency of nucleotide metabolites: potential role in ischemia-induced vascular growth. 252 26

The crystal and molecular structures of methyl 2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-1,4- dihydropyridine-3-carboxylate and ethyl 4-(2-difluoromethoxyphenyl)-1,4,5,7,-tetrahydro-2-methyl-5-oxof uro[3,4-b]pyridine-3-carboxylate, which are analogs of the calcium channel antagonist nifedipine reported to have agonist activity, have been determined. The conformations of these two agonists are compared with the conformational features shown by nifedipine and related 1,4-dihydropyridine calcium channel antagonists. Common conformational features shown by these agonists and antagonists allow both to bind to the same plasma membrane receptor while subtle differences in hydrogen-bonding activity of the amine group, and ester group orientation and hydrophobic fit, may control the availability of channel open and closed states.
Mol Pharmacol 1985 May
PMID:Conformational features of calcium channel agonist and antagonist analogs of nifedipine. 258 Nov 23

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, increases membrane chloride conductance. Previously, we reported that GABA increases 36Cl- uptake by membrane vesicles (microsacs) prepared from mouse brain. Employing this technique, we found that the GABAA agonists, muscimol, isoguvacine, 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridine-3-ol, and 3-amino-1-propane sulfonate, all produced a concentration-dependent increase in 36Cl- influx, but baclofen, a GABAB agonist, failed to alter 36Cl- flux. Inhibition of GABA-dependent 36Cl- influx was produced by the convulsant drugs, bicuculline, picrotoxin, and pentylenetetrazole. Ion specificity was demonstrated by a failure of GABA agonists to stimulate influx of 45Ca2+, 86Rb+, 22Na+, or 35SO4(2). GABA-stimulated uptake of 36Cl- was largest in cortex and cerebellum and smaller in hippocampus and striatum. There was little difference in sensitivity to GABA among the areas. Analysis of subcellular fractions prepared from mouse brain demonstrated that the GABA-dependent 36Cl- influx was enriched in the synaptosomal fraction. The nonspecific (GABA-independent) uptake of 36Cl- was enriched in the myelin fraction. These experiments provide evidence for a functional coupling among GABA receptors and the chloride ionophore and suggest that the GABA-activated chloride channel is a site of action for several convulsant compounds.
Mol Pharmacol 1986 May
PMID:gamma-Aminobutyric acid agonists and antagonists alter chloride flux across brain membranes. 301 78

Control of mitochondrial respiration depends on ADP availability to the F1-ATPase. An electrochemical gradient of ADP and ATP across the mitochondrial inner membrane is maintained by the adenine nucleotide translocase which provides ADP to the matrix for ATP synthesis and ATP for energy-dependent processes in the cytosol. Mitochondrial respiration is responsive to the cytosolic phosphorylation potential, ATP/ADP.Pi which is in apparent equilibrium with the first two sites in the electron transport chain. Conventional measures of free adenine nucleotides is a confounding issue in determining cytosolic and mitochondrial phosphorylation potentials. The advent of phosphorus-31 nuclear magnetic resonance (P-31 NMR) allows the determination of intracellular free concentrations of ATP, creatine-P and Pi in perfused muscle in situ. In the glucose-perfused heart, there is an absence of correlation between the cytosolic phosphorylation potential as determined by P-31 NMR and cardiac oxygen consumption over a range of work loads. These data suggest that contractile work leads to increased generation of mitochondrial NADH so that ATP production keeps pace with myosin ATPase activity. The mechanism of increased ATP synthesis is referred to as 'stimulus-response-metabolism' coupling. In muscle, increased contractility is a result of interventions which increase cytosolic free Ca2+ concentrations. The Ca2+ signal thus generated increases glycogen breakdown and myosin ATPase in the cytosol. This signal is concomitantly transmitted to the mitochondria which respond to small increases in matrix Ca2+ by activation of Ca2+-sensitive dehydrogenases. The Ca2+-activated dehydrogenase activities are key rate-controlling enzymes in tricarboxylic acid cycle flux, and their activation by Ca2+ leads to increased pyridine nucleotide reduction and oxidative phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem 1988 Jun
PMID:Control of mitochondrial respiration in muscle. 305 Apr 50


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