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M Hirobe

Publications and source records attributed to M Hirobe.

At least 73 records · Page 4Linked to original sources
PubMed1992

Effects of oxygen concentration on the metabolism of anisole homologues by rat liver microsomes.

1. The effects of oxygen concentration were studied on the metabolic pathways of anisole homologues (anisole, phenetole and isopropoxybenzene) catalysed by liver microsomes from phenobarbital-treated rats. 2. With increase of oxygen concentration, the rate of anisole o-hydroxylation reached a plateau at about 35 microM O2, while the rates of O-demethylation and aromatic p-hydroxylation were still increasing at 223 microM O2 (air). 3. The rates of all three metabolic reactions of phenetole reached plateau levels at about 80 microM O2. 4. The rates of all three metabolic reactions of iso-propoxybenzene were still increasing as 223 microM O2 (air). 5. The ratio of aromatic p-hydroxylation or O-dealkylation to aromatic o-hydroxylation decreased in anisole metabolism, and showed no uniform change in phenetole and isopropoxybenzene metabolism with decreasing oxygen concentration. 6. The ratio of aromatic p-hydroxylation to O-dealkylation was essentially constant over the range of oxygen concentration studied in anisole and phenetole metabolism, while in iso-propoxybenzene metabolism the ratio was different between higher and lower oxygen concentrations than 60 microM. 7. This series of compounds with increasing chain length did not show homologous changes in rates of product formation or O2 dependent of product formation.

Animals↗
PubMed1991

Amphetamine-antagonistic properties of 4-phenyl-1,2,3,4- tetrahydroisoquinoline: inhibition of spinal reflex-enhancing effects of methamphetamine, phenylethylamine and nomifensine.

The antagonistic effects of 4-phenyl-1,2,3,4-tetrahydroisoquinoline (4PTIQ) against S(+)-methamphetamine, phenylethylamine and nomifensine were studied by measurement of spinal monosynaptic reflex potential (MSR). S(+)-Methamphetamine, phenylethylamine and nomifensine enhanced the amplitude of MSR in C1-spinalized rats through release of noradrenaline from the terminals of descending fibers and consequent activation of alpha 1-adrenoceptors. Although 4PTIQ alone did not change the amplitude of the MSR, 4PTIQ inhibited the enhancement of MSR induced by S(+)-methamphetamine and related compounds. The MSR of rats with an intact spinal cord was enhanced by conditioning stimulation of the ipsilateral locus ceruleus. The MSR enhancement produced by the stimulation was blocked by prazosin but unaffected by 4PTIQ, showing that 4PTIQ does not have an alpha 1-blocking action. These results suggest that the antagonistic effects of 4PTIQ on MSR enhancement by S(+)-methamphetamine, phenylethylamine and nomifensine are due to its blocking of noradrenaline release produced by these amphetamine-like agents.

Amphetamine↗
PubMed1991

Effects of oxygen on the relative photodissociability of cytochrome P-450.CO complex in rat liver microsomes.

Flash photolysis of cytochrome P-450 in phenobarbital-induced rat liver microsomes was examined by observing the decay of absorbance change, A(t), at 450 nm after photolysis of the heme.CO complex by a depolarized laser flash. The relative photodissociability, A(0)/Ab, is significantly decreased upon an increase in oxygen concentration. A(0)/Ab is 96%, 86%, and 51% at oxygen concentrations of 90, 115, and 155 microM when compared with A(0)/Ab at 0 microM O2. In the presence of aminopyrine, the oxygen-dependent decrease in the relative photodissociability was enhanced about 2 times. The rate of CO recombination with cytochrome P-450 was decreased by increasing O2 concentration. By going from 0 to 155 microM O2, about 17% decrease and 58% decrease in the recombination rate were observed in the absence and presence of aminopyrine, respectively. In the absence of CO, no absorbance change A(t) at 450 nm was observed even at 155 microM O2, excluding a possible contribution of P-450.O2. The present observation leads to the speculation that oxygen molecules around the heme.CO complex affect the electronic state of the heme, resulting in an increase in Fe-CO bond strength.

Aminopyrine↗
PubMed1991

1-Methyl-1,2,3,4-tetrahydroisoquinoline, decreasing in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse, prevents parkinsonism-like behavior abnormalities.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse brain, there was no significant increase or decrease in the content of an endogenous amine, 1,2,3,4-tetrahydroisoquinoline (TIQ), which is well noted for inducing parkinsonism, whereas another endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ), was markedly reduced. This result agrees with the finding in human idiopathic parkinsonianism, confirmed by our previous research. In addition, pretreatment with 1-MeTIQ completely prevented MPTP- or TIQ-inducing bradykinesia, a symptom of parkinsonism. This study confirmed that 1-MeTIQ plays an important role in preventing the pathogenesis of parkinsonism and is a possible leading compound of anti-parkinsonism agents.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Formation of superoxide by benzofurazans in Escherichia coli under aerobic incubation.

The superoxide (O2-.) production in Escherichia coli through the action of benzofurazans (BZs) was examined using the cytochrome c (cyt. c) reduction method. Adding BZs to E. coli cell suspensions caused the cyt. c reduction, which was completely inhibited by superoxide dismutase (SOD). The effects of BZs on cyt. c reduction was in the order of benzofurazan (1) approximately 4,7-dimethylbenzofurazan (2) approximately 4,7-dibromobenzofurazan (3) less than 4-bromo-6-cyanobenzofurazan (4) less than 4,7-dicyanobenzofurazan (5). This was correlated with the toxicity of BZs against E. coli growth (1 approximately 2 approximately 3 less than 4 less than 5) and with the redox potentials of BZs (1 approximately 2 less than 3 less than 4 less than 5). The formation of compound 5 anion radical in the cell suspensions in the absence of dioxygen (O2), was determined using ESR spectrum. The ESR signal of the anion radical disappeared with the addition of O2. The BZs effected the O2-. production in E. coli cells.

Aerobiosis↗
PubMed1991

Novel iron complexes behave like superoxide dismutase in vivo.

Novel iron and copper complexes having tris[N-(5-methyl-2-pyridylmethyl)-2-aminoethyl]amine (5MeT-PAA), tris[N-(3-methyl-2-pyridylmethyl)-2-aminoethyl]amine (3MeTPAA), tris[N-(5-methoxycarbonyl-2-pyridylmethyl)-2-aminoethyl]amine (TNAA), tris[(2-thienylmethyl)-2-aminoethyl]amine (TTAA), tris[(2-furylmethyl)-2-aminoethyl]amine (TFAA) or tris[(2-imidazoyl)-2-aminoethyl]amine (TIAA) as ligand, were synthesized to examine the superoxide dismutase (SOD) activity. The concentrations of Fe-3MeTPAA and Fe-TIAA equivalent to 1 unit of SOD (IC50) were 0.5 microM and 1.0 microM, respectively. Fe-3MeTPAA and Fe-TIAA had higher SOD activity than other Fe and Cu complexes and protected Escherichia coli cells from paraquat toxicity. In case of using tris[N-(6-methyl-2-pyridylmethyl)-2-aminoethyl]amine (6MeTPAA) as ligand, the Fe complex could not be obtained, which may be due to the steric hindrance of 6-methyl substituent. Generally, Cu complexes had low SOD activity, compared with Fe complexes, and could not suppress paraquat toxicity.

Copper↗
PubMed1990

3-Hydroxycoumarins: first direct preparation from coumarins using a Cu2(+)-ascorbic acid-O2 system, and their potent bioactivities.

First direct 3-hydroxylation of a coumarin ring via a purely chemical system, previously only possible using cytochrome P-450, was successfully conducted by a Cu2(+)-ascorbic acid-O2 system; the two 3-hydroxycoumarins obtained were novel compounds, 3-hydroxyscopoletin and 3-hydroxyisoscopoletin. 5-Lipoxygenase and alpha-D-glucosidase inhibitory activities of coumarins greatly increased through 3-hydroxylation. 3-Hydroxyscopoletin and 3-hydroxyumbelliferone had a high inhibitory potency for 5-lipoxygenase and for alpha-D-glucosidase respectively; they serve as lead compounds for new drugs.

Arachidonate 5-Lipoxygenase↗
PubMed1990

Confirmation of the enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chromatography/mass spectrometry with negative ion chemical ionization.

With the aid of a new chiral derivatizing reagent and a sensitive and specific assay using capillary gas chromatography/negative ion chemical ionization mass spectrometry, the proportions of R and S enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) in mammalian tissues and foods were studied. R- and S-1MeTIQ enantiomers derivatized with a chiral derivatizing reagent, perfluoro-2-propoxypropionylchloride, were clearly separated. The ratio of enantiomers was R/S = 0.24, 0.55 and 0.60 in wine, cocoa and mouse brain. S-1MeTIQ predominated in all samples. This result suggested that 1MeTIQ could be formed at least partially through an enzymatic mechanism.

Animals↗
PubMed1990

Metabolism and brain accumulation of tetrahydroisoquinoline (TIQ) a possible parkinsonism inducing substance, in an animal model of a poor debrisoquine metabolizer.

4-Hydroxytetrahydroisoquinoline (4OH-TIQ) was detected as a metabolite of a possible parkinsonism-inducing substance, tetrahydroisoquinoline (TIQ), in rat liver microsomes and rat urine. Urinary excretion of 4OH-TIQ was significantly reduced in female DA rat, an animal model of a poor debrisoquine metabolizer. The female DA rat also showed significantly higher brain accumulation of TIQ. These results suggest that the metabolic detoxication process is depressed and TIQ accumulation in the brain is enhanced in a poor debrisoquine metabolizer, which may be one possible explanation for poor debrisoquine metabolizers being susceptible to Parkinson's disease.

Animals↗
PubMed1990

A novel and neurotoxic tetrahydroisoquinoline derivative in vivo: formation of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, a condensation product of amphetamines, in brains of rats under chronic ethanol treatment.

Repeated amphetamine administration to rats under chronic ethanol intoxication resulted in the formation of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (1,3-DiMeTIQ), a novel metabolite of amphetamines. 1,3-DiMeTIQ was quantified with a sensitive, specific assay using gas chromatography-mass spectrometry. It was not found in the brains of rats given repeated amphetamine administration but no ethanol. The chronic ethanol-intoxicated rats subjected to repeated amphetamine administration exhibited behavioral abnormalities, such as repeated convulsions and curving of the back. 1,3-DiMeTIQ contents were markedly higher in the brain or plasma of rats manifesting abnormal behavior in comparison with those in rats behaving normally. Thus, the 1,3-DiMeTIQ content in the rat brain seems to have some relationship with behavioral abnormalities. This study also confirmed that 1,3-DiMeTIQ can cross the blood-brain barrier in the rat. Intraperitoneal 1,3-DiMeTIQ injections to rats caused behavioral symptoms similar to those observed in rats with chronic ethanol intoxication and repeated amphetamine administration. The effect of toxic doses of 1,3-DiMeTIQ on dopaminergic and serotonergic metabolism in the whole rat brain was also investigated.

Alcoholism↗
PubMed1990

Toxicities of dicyanobenzofurazans with formation of superoxide in Escherichia coli.

The toxicities of some benzofurazans (BZs), benzofurazan (1), 4,7-dimethylbenzofurazan (2), 4,7-dibromobenzofurazan (3), 4-bromo-6-cyanobenzofurazan (4), 4,7-dicyanobenzofurazan (5) and 4,5-dicyanobenzofurazan (6), were examined on Escherichia coli. Compound 5 at 4 microM and compound 6 at 7 microM completely inhibited the growth of E. coli in a simple nutritionally restricted medium (GM medium). These compounds were more toxic in GM medium than in a nutritionally rich medium (YE medium), which contained yeast extract as an additive in GM medium. Compound 4 also inhibited the growth of E. coli at 300 microM in GM medium. The toxicities of BZs were in the order of 1 approximately 2 approximately 3 less than 4 approximately 5 approximately 6. Compounds 4, 5 and 6 induced manganese-superoxide dismutase (Mn-SOD) and catalase activities of E. coli in YE medium. The induced SOD and catalase provide a defense against the potential cytotoxicities of O2- and H2O2. The rate of dioxygen uptake in cyanide-resistant respiration of E. coli was dependent on the concentration of 5, and was correlated with the induction of SOD and catalase. The reduction potentials of BZs followed the order of 1 approximately 2 less than 3 less than 4 less than 5 approximately 6. Compounds 5 and 6, which had redox potentials higher than those of the other BZs, are thought to be more readily reduced in the living system.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzoxazoles↗
PubMed1990

Application of chemical P-450 model systems to study drug metabolism. III. Metabolism of 3-isobutyryl-2-isopropylpyrazolo[1,5-alpha]pyridine.

Oxidation of 3-isobutyryl-2-isopropylpyrazolo[1,5-alpha]pyridine (IBPP) was carried out with various chemical model systems for cytochrome P-450 in comparison with the liver microsomal system of rats or humans. Alpha-hydroxylation of side chains and ring hydroxylation at the 6 and 7 positions were the main reactions in both systems. A pattern analysis of products using two dimensional thin layer chromatography was employed to compare the functions of the chemical model systems with those of microsomal systems. The reaction profile of IBPP by the catalyst/Pt-colloid/H2, O2 system was most similar to that of human or rat microsomal system. The utility of these chemical models is discussed from the viewpoint of drug metabolism.

Animals↗
PubMed1990

Increasing 5-lipoxygenase inhibitory activities by oxidative conversion of o-methoxyphenols to catechols using a Cu2(+)-ascorbic acid-O2 system.

Several complicated o-methoxyphenols were oxidized with high selectivity to catechols by a Cu2(+)-ascorbic acid-O2 system. In this way, the RBL-1 5-lipoxygenase inhibitory activities of o-methoxyphenols were greatly increased. [6]-Norgingerol (4), a novel compound derived from [6]-gingerol (3), shows promise as a lead compound for new drugs because of its high inhibitory potency (IC50 = 5.0 x 10(-8) M).

Anisoles↗
PubMed1989

Superoxide dismutase mimics based on iron in vivo.

Novel metal complexes, Fe(II)-tetrakis-N,N,N',N' (2-pyridylmethyl)ethylenediamine(Fe-TPEN) and Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl]amine (Fe-TPAA), catalyzed the dismutation of superoxide, and 0.8 microM Fe-TPEN and 7.5 microM Fe-TPAA were equivalent to 1 unit of superoxide dismutase (SOD) activity in the xanthine oxidase-cytochrome c assay. Addition of serum albumin had no effect on the activities of Fe-TPEN and Fe-TPAA but depressed those of the Cu(salicylate)2 and Cu(diisopropylsalicylate)2 complexes. Both iron complexes blocked the toxic effect of paraquat on Escherichia coli growth and survival without causing induction of SOD. In contrast, this behavior was not seen with other SOD mimics containing copper or manganese. These results support the view that the SOD activities of these iron complexes remain intact in living cells.

Chelating Agents↗
PubMed1989

Dioxathiadiaza-heteropentalenes mediate superoxide and hydrogen peroxide production in Escherichia coli.

The dioxathiadiaza-heteropentalenes, HEP-I (4,4-dimethyl-1,7-dioxa-2,6-diaza- 7 alpha lambda 4-thia-3H,5H-benzo[cd]pentalene), HEP-II (1,7-dioxa-2, 6-diaza-4, 7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene), HEP-III (1,7-dioxa-2,6-diaza-4, 7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene-4-oxide), and HEP-IV (1,7-dioxa-2,6-diaza-4,7 alpha lambda 4-dithia-3H, 5H-benzo[cd]pentalene-4,4-dioxide), inhibited growth of Escherichia coli in a simple glucose-salt medium, with their toxicities following the order of HEP-IV greater than HEP-III greater than HEP-II greater than HEP-I. These toxicities could be suppressed by yeast extract added to the glucose-salt medium. Yeast extract also facilitated maximal induction of superoxide dismutase (SOD) and catalase. The redox potentials of HEP-I-HEP-IV and the rates of oxygen uptake dependent on heteropentalenes in cyanide-resistant respiration of E. coli were correlated with the induction of SOD and catalase. Thus, the higher the redox potential of the compounds, the more potent they were for induction of enzyme production. Under anaerobic conditions, HEP-IV did not inhibit E. coli growth. These results indicate that HEP-I-HEP-IV can be reduced within the cell of E. coli and then reoxidized by molecular oxygen, generating O2- and H2O2. The toxicities of the heteropentalenes depend largely upon superoxide and/or hydrogen peroxide toxicity, and SOD and catalase provide a defense against the potential cytotoxicity of these species.

Aerobiosis↗
PubMed1989

Kappa-receptor mechanisms in synaptosomal Ca uptake.

1. Inhibition of Ca uptake by certain opioids was tested in synaptosomes of rat brain. The potency order was dynorphin A 1-13, a kappa-selective agonist greater than nalorphine greater than nalorphine epoxide greater than morphine. 2. The pA2 values (negative logarithms of dissociation constant) of naloxone against four opioids were not significantly different from each other, suggesting that the site of action of the four opioids is identical. 3. Morphiceptin, a mu-selective agonist and DADLE, a delta-selective agonist had no effect on Ca uptake. 4. These results suggest that the site of action of the four opioids is kappa-receptors. 5. Potency order estimated from competition inhibition curves of specific binding of [3H]ethylketo-cyclazocine (kappa-selective ligand) by the test opioids was nalorphine greater than nalorphine epoxide greater than dynorphin A 1-13 greater than morphine. 6. The difference between the two potency orders suggests that affinities and intrinsic activities of the drugs are important factors in determining their agonistic activity in kappa-receptor mechanisms.

Animals↗
PubMed1989

Effect of tetrahydroisoquinoline (TIQ), one of endogenous substances inducing parkinsonism, on isolated rat vas deferens.

1. The effect of tetrahydroisoquinoline (TIQ) was examined on isolated rat vas deferens. 2. TIQ shifted the concentration-response curve for norepinephrine towards lower concentrations: the pD2-value of norepinephrine in the presence of TIQ was significantly greater than in its absence. 3. Tyramine-induced contraction in the presence of TIQ decreased by a significant 35% more than in the absence of TIQ. 4. These results indicate that the pharmacological effect of TIQ is due to the inhibition of the neuronal uptake of catecholamines.

Animals↗