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Biomedical subjects

P H Yu

Publications and source records attributed to P H Yu.

At least 127 records · Page 7Linked to original sources
PubMed1991

Enzymatic N-methylation of phenelzine catalyzed by phenylethanolamine N-methyltransferase.

1. Phenelzine has been found to be methylated by enzymes obtained from bovine adrenal and some rat tissues in the presence of S-adenosylmethionine (SAM) as methyl group donor. 2. The methylated product was chromatographically (TLC and HPLC) identical with chemically synthesized N-methylphenelzine. The structure of this methylated phenelzine has been confirmed by a GC-MS procedure. 3. The phenelzine methyltransferase in the bovine adrenal has a molecular weight and isoelectric point identical with that of bovine adrenal phenylethanolamine N-methyl-transferase (PNMT). 4. Methylated phenelzine possesses much reduced inhibitory activity towards monoamine oxidase (MAO). It can, however, be deaminated by MAO to produce phenylacetaldehyde, and subsequently phenylacetic acid. 5. Other hydrazine compounds, such as hydralazine, have also been found to be methylated by the adrenal enzyme. 6. Our finding of enzymatic methylation of hydrazine compounds is novel, and it may play a role in the metabolism of hydrazine drugs.

Adrenal Medulla↗
PubMed1990

Some pharmacological implications of MAO-mediated deamination of branched aliphatic amines: 2-propyl-1-aminopentane and N-(2-propylpentyl)glycinamide as valproic acid precursors.

2-Propyl-1-aminopentane (2-PAP) and N-(2-propylpentyl)glycinamide (PPG) were readily deaminated by rat liver monoamine oxidase B and rat aorta semicarbazide-sensitive amine oxidase. The deaminated product, valproic acid (VPA), was identified by HPLC-fluorometric assessment. Absorption and biotransformation of these compounds and their VPA metabolite into the brain were rapid processes. An investigation was conducted to examine whether these compounds can be used as VPA prodrugs. Both compounds, however, at relatively low doses exhibited distinct tremor effects in mice and rats. They also potentiate the convulsant effect induced by mercaptopropionic acid (MPA).

3-Mercaptopropionic Acid↗
PubMed1990

Effect of trimipramine, an atypical tricyclic antidepressant, on the activities of various enzymes involved in the metabolism of biogenic amines.

1. The mechanism of action of trimipramine, a clinically efficacious tricyclic antidepressant, is not well understood. In order to investigate whether it might affect the activities of different enzymes involved in biogenic amine metabolism we have undertaken a comparative study of it along with amitriptyline. 2. Neither trimipramine nor amitriptyline, at concentrations up to 1 mM, exhibited any significant effect on phenylalanine hydroxylase, tyrosine hydroxylase, L-aromatic amino acid decarboxylase, dopamine-beta-hydroxylase, phenylethanolamine-N-methyltransferase, catechol-O-methyltransferase, phenylsulfotransferase or tyrosine aminotransferase. 3. Monoamine oxidase, however, was inhibited by both drugs with the greatest effect being on MAO-B. The inhibition was reversible, non-competitive and relatively weak.

Adrenal Glands↗
PubMed1990

Cutaneous vasomotor sensitivity to ethanol and acetaldehyde: subtypes of alcohol-flushing response among Chinese.

A cutaneous test has been applied in examination of the flushing response to ethanol and acetaldehyde in 402 Chinese of Han ethnicity. Using this noninvasive method, five response subtypes have been observed: (A) fast flushing to both ethanol and acetaldehyde; (B) fast flushing only to ethanol but not to acetaldehyde; (C) slow flushing to ethanol only; (D) no response either to ethanol or to acetaldehyde; (E) vasoconstriction to ethanol, or to both ethanol and acetaldehyde. A total of 94% in subtype (A) are reported to be flushers, while only 25% was reported in subtype (D). Other physiological responses, such as tachycardia, dizziness, headache, drowsiness, and nausea are less frequent after alcohol ingestion. The recent history of consumption of alcohol of the subjects in different subtypes was also obtained. Although alcohol-induced flushing is thought to be a deterrent factor to heavy consumption of alcohol, the frequency of drinking of alcoholic beverages was not found to be different between flushers and nonflushers.

Acetaldehyde↗
PubMed1990

Oxidative deamination of aliphatic amines by rat aorta semicarbazide-sensitive amine oxidase.

Rat aorta semicarbazide-sensitive amine oxidase (SSAO) exhibits very high affinity in the deamination of an homologous series of aliphatic amines of 1 to 18 straight chain carbon atoms. The Km value decreases substantially as the chain length of these amines increases. The Vmax values are higher for the short chain amines. Diamines are poor substrates for SSAO or are not acted upon by the enzyme. The substrate preference for SSAO differs from that for monoamine oxidase.

Amine Oxidase (Copper-Containing)↗
PubMed1989

Deuterium isotope effect of phenelzine on the inhibition of rat liver mitochondrial monoamine oxidase activity.

Phenelzine is a suicide monoamine oxidase (MAO) inhibitor with antidepressant properties. The present study compares the inhibition of rat liver mitochondrial MAO by phenelzine and 1,1-dideuterated phenelzine and the metabolism of these drugs by that enzyme. Phenylacetaldehyde, which was measured by a high performance liquid chromatographic procedure, was found to be the major metabolite of phenelzine after incubation with MAO. The time-courses of aldehyde formation were non-linear due to the time-dependent inhibition of MAO. The reaction rate was reduced substantially when the hydrogen atom in the 1-carbon position was replaced by deuterium. The VH/VD value was 3.1, indicating a primary isotope effect. Such a substitution of deuterium in the phenelzine molecule did not affect significantly the initial reversible inhibition of MAO, which was determined by comparison of their Ki values. The irreversible inhibition, as estimated from IC50 values, however, was potentiated substantially by deuteration. These results support the notion that the irreversible inhibition of MAO activity by phenelzine proceeds via a phenylethyldiazene intermediate, which reacts with the enzyme to form a covalent adduct. An alternative pathway involving hydrogen abstraction from carbon-1 of phenelzine or via rearrangement of the diazine on the enzyme surface could occur to form a phenylethylidene hydrazine intermediate which would subsequently be hydrolyzed to phenylacetaldehyde. The reduction in the rate of phenylethylidene hydrazine formation due to the isotope effect could lead to the accumulation of phenylethyldiazene intermediate and thus potentiate the inhibition of MAO activity.

Acetaldehyde↗
PubMed1989

Enhancement of 5-HT-induced anorexia: a test of the reversibility of monoamine oxidase inhibitors.

Subcutaneous injection of 1 mg/kg 5-hydroxytryptamine (5-HT) reduced the intake of a 10% sucrose solution in rats. A single injection of the monoamine oxidase inhibitor (MAOI) clorgyline enhanced the anorectic effect of 5-HT. Such an effect persists 2, 24, 48, 72 and 96 h after injection. The clorgyline treatment almost completely inhibited type A MAO activity in the liver at 2 h post-injection. By 120 h, the time at which potentiation of 5-HT induced anorexia disappeared, MAO-A activity had returned to 80% of control values. These results demonstrate that the clorgyline effect is long-lasting and irreversible. Brofaromine (5 mg/kg) and cimoxatone (20 mg/kg) also enhanced the anorectic effect of 5-HT injected 2 h later. The potentiating effects of brofaromine and cimoxatone were not observed when 5-HT was administered 24 h later. These results indicate that brofaromine and cimoxatone are short-acting, reversible inhibitors of MAO-A activity in vivo. Moclobemide (30 mg/kg) failed to enhance the anorectic action of 5-HT injected 2 and 24 h later. The potentiation of 5-HT induced anorexia may be a useful behavioural test for investigating the degree of reversibility, and time course of action of MAOIs.

Animals↗
PubMed1989

Development of monoamine oxidase activity and monoamine effects on glutamate release in cerebellar neurons and astrocytes.

Activities of monoamine oxidase (MAO) A and B were measured during the first month of postnatal development in mouse cerebellum and in primary cultures of either cerebellar granule cells or cerebellar astrocytes, derived from 7-day-old cerebella. In addition, effects of the two monoamines, serotonin (a MAO A substrate) and phenylethylamine (a MAO B substrate) on the release of glutamate under resting conditions and in a transmitter related fashion (i.e., potassium-induced, calcium-dependent glutamate release) were studied during the same period. Both MAO A and MAO B activities increased during in vivo development (beginning around postnatal day 14) and in cultured astrocytes (during a comparable time period and to a similar extent), but remained constant at a low level in granule cells. In 4-day-old cerebellar granule cell cultures there was no potassium-induced glutamate release but serotonin as well as phenylethylamine reduced the release in both the presence and absence of excess potassium. In 8- and 12-day-old granule cell cultures and in 8- and 18-day old astrocyte cultures there was a pronounced glutamate release during superfusion with 50 mM K+. In both neurons and astrocytes this response was inhibited by 1 nM of either serotonin or phenylethylamine. In the astrocytes the inhibition was followed by an increased release of glutamate in both the presence and absence of the high potassium concentration, whereas the 8-day-old neurons showed only a slight increase in glutamate release after the withdrawal of the monoamine and only in the absence of excess potassium. The response was almost identical in 8- and 18-day-old astrocytes in spite of the marked difference in MAO activities.

Animals↗
PubMed1989

Determination of plasma pyridoxal 5'-phosphate by an enzymatic-high-performance liquid chromatographic procedure.

An enzymatic-HPLC procedure for the determination of plasma pyridoxal 5'-phosphate (PLP) has been established. The assay is based on the decarboxylation of L-3,4-dihydroxyphenylalanine using Streptococcus tyrosine decarboxylase apoenzyme, which requires PLP as cofactor. The product of the enzyme reaction, dopamine, is measured by Coulochem electrochemical detection with a series of oxidizing and then reducing electrodes. Trace amounts of PLP in the apoenzyme preparation were removed with the aid of cysteine-sulfinic acid and gel filtration. The detection limit for PLP by this method is 50 pM in plasma.

Chromatography, High Pressure Liquid↗
PubMed1989

Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B.

Monoamines with from 1 to 18 straight chain carbon atoms have been analysed as rat liver monoamine oxidase substrates. Methylamine and ethylamine are clearly not substrates of monoamine oxidase (MAO). n-Propylamine, n-butylamine, n-dodecylamine and n-octadecylamine are relatively poor substrates, i.e. with high Km and low Vmax values for the enzyme. n-Pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine and n-decylamine are all very good MAO substrates. All these aliphatic amines are found to be typical type B substrates according to the sensitivities of the enzyme towards the selective MAO-B inhibitor selegiline and the MAO-A inhibitor, clorgyline. The sensitivity towards selegiline with respect to these amines is even higher, i.e. Ki = 1 x 10(-9) M for butylamine, than that of the typical type B substrate beta-phenylethylamine (Ki = 1 x 10(-8) M). The sensitivity towards selegiline decreases slightly with increasing chain length of these aliphatic amines.

Amines↗
PubMed1988

Interaction of biogenic amines with components of cigarette smoke. Formation of cyanomethylamine derivatives.

A reaction of the biogenic amines 5-hydroxytryptamine, dopamine, histamine, p-tyramine, beta-phenylethylamine and tryptamine with components of cigarette smoke was observed. The adducts formed from 5-hydroxytryptamine and beta-phenylethylamine were purified by chromatographic procedures and identified by high resolution mass spectrometry. The structures of some of these compounds were established as cyanomethylamine derivatives, i.e. RCH2CH2NHCH2CN. In the case of 5-hydroxytryptamine, a cyanomethyl-beta-1,2,3,4-tetrahydrocarboline product formed via a Pictet-Spengler condensation reaction was isolated. The mass spectra of such adducts and their fragment ions were observed to be identical to those of chemically synthesized cyanomethylamines. Both formaldehyde and cyanide, which are known to be present in cigarette smoke, were involved in the reaction with the primary amines. The reaction was time dependent and was enhanced by an increase in temperature or by incubation under alkaline conditions. Cyanomethyl adduct formation was increased when smoke from cigarettes with higher tar and nicotine content was used. When the amines were incubated with human saliva obtained after cigarette smoking, cyanomethylamine products were readily detected.

Acetonitriles↗
PubMed1988

Monoamine oxidase-B inhibition: a comparison of in vivo and ex vivo measures of reversible effects.

A behavioural test involving potentiation of the effects of an acute injection of beta-phenylethylamine (10 mg kg-1 i.p.) was used to assess the time-course of type-B MAO inhibition after administration of (--)deprenyl (5 mg kg-1 i.p.) and of MD 240928 (20 mg kg-1 i.p.) respectively. Potentiation of the effects of beta-phenylethylamine was observed 1 h after injection of (-)deprenyl or MD 240928. This effect was still evident 120 h after administration of (-)deprenyl but not 24 h after administration of MD 240928. Comparisons of ex vivo estimates of MAO activity yielded a corresponding time-course for the recovery of this enzyme. The extent of MAO inhibition required for potentiation of the effects of beta-phenylethylamine was inferred from a comparison of the behavioural test results and the ex vivo MAO activity observed after (-)deprenyl administration. These comparisons indicate a significant underestimation of MD 240928-induced MAO inhibition using ex vivo measures. This underestimation is interpreted as evidence for dilution effects in the ex vivo assay of MAO inhibition. The potentiation of effects of beta-phenylethylamine under the present conditions is proposed as a useful and simple test for effects of reversible type-B MAO inhibitors.

Animals↗
PubMed1988

Stereospecific deamination of benzylamine catalyzed by different amine oxidases.

1. Stereospecific deuterated benzylamine enantiomers, R(alpha-2H1)-and S(alpha-2H1)-benzylamine, were synthesized by a combined chemical and enzymatic method. 2. The retention or cleavage of the deuterium atom during deamination of benzylamine catalyzed by amine oxidases from different sources was assessed by a GC-MS procedure and confirmed by HPLC separation of the products and by the observation of a deuterium isotope effect. 3. Three types of stereospecific abstraction of hydrogen atoms from the alpha-carbon of benzylamine during deamination were observed: (a) In the first type of deamination the pro-R hydrogen is removed from the alpha-carbon. Enzymes in this category are mitochondrial MAO from different tissues; (b) The second type of deamination involves the abstraction of pro-S hydrogen. Soluble enzymes such as rat aorta benzylamine oxidase or diamine oxidase from hog kidney and pea seedling have been found to belong to this group; and (c) Bovine plasma amine oxidase exhibits the third type of deamination where no absolute stereospecificity is required. 4. The kinetic deuterium isotope effect during the deamination of benzylamine by the different amine oxidase varies greatly, i.e. VH/VD ranged from 1.7 to 4.0.

Amine Oxidase (Copper-Containing)↗
PubMed1988

Formation of cyanomethyl derivatives of basic amino acids and proteins with components in cigarette smoke.

A reaction of the basic amino acids, lysine and arginine, with components of cigarette smoke has been observed. The adducts produced have been identified as cyanomethyl derivatives. Both formaldehyde and cyanide, which are known to be present in cigarette smoke, are involved in the reaction with the primary amino group. The reaction is time-dependent and can be enhanced by an increase of temperature or by incubation under alkaline conditions. Cyanomethyl adduct formation was found to be increased when smoke from cigarettes with higher tar and nicotine content was used. When proteins, such as bovine serum albumin, trypsin inhibitors or crude rat lung proteins were incubated with the cigarette smoke solution, new protein adducts with increased pI values were produced which are separable from the original proteins by gel isoelectric focussing. Radioisotopically labelled cyanide can be irreversibly linked to protein and the linkage is enhanced in the presence of formaldehyde.

Arginine↗
PubMed1988

Three types of stereospecificity and the kinetic deuterium isotope effect in the oxidative deamination of dopamine as catalyzed by different amine oxidases.

When the stereospecifically deuterated dopamine enantiomers, (R)- and (S)-[alpha-2H1]dopamine, are incubated with amine oxidases, the deuterium atom may be either retained to form monodeuterated 3,4-dihydroxyphenylacetaldehyde, or eliminated to produce the nondeuterated or protio-aldehyde product. These two aldehydes can be separated from one another and identified by high-performance liquid chromatography with electrochemical detection. Three types of stereospecific abstraction of a hydrogen from the alpha-carbon of dopamine during deamination have been observed. In the first type, the pro-R hydrogen is removed from the alpha-carbon. Enzymes in this category are mitochondrial monoamine oxidases A and B, as isolated from different tissues and species. The second type of deamination involves the abstraction of pro-S hydrogen from the alpha-carbon of dopamine. Soluble enzymes, such as rat aorta benzylamine oxidase or diamine oxidase from hog kidney and pea seedling, have been found to belong to this group. Bovine plasma amine oxidase exhibits the third type of deamination where no absolute stereospecificity is required. This enzyme catalyzes the oxidation of either (S)- or (R)-[alpha-2H1]dopamine, preferably breaking the C-H bond rather than the C-2H bond in both cases. The kinetic deuterium isotope effect during the deamination of dopamine catalyzed by the different amine oxidases varies greatly; VH/VD ranges from 1.5 to 5.5. The high magnitude of the isotope effect suggests that hydrogen abstraction may be the rate-limiting step (i.e., in reactions catalyzed by benzylamine oxidase and monoamine oxidase). When the isotope effect is low (i.e., for diamine oxidases from hog kidney or pea seedling), it is uncertain if the breaking of the bond is rate limiting.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Inapparent infection of hepatitis A virus.

To detect inapparent infection with hepatitis A virus, serial sera were collected from patients with hepatitis A and their contacts in two waterborne epidemics in China. Epidemic 1 occurred in a rural village near Hangzhou during August 1978-January 1979, and epidemic 2 took place in a rural primary school in Pinghu County in Zhejiang in April-May 1985. These sera were tested for antibodies against hepatitis A virus (anti-HAV), serum glutamic pyruvic transaminase (SGPT) activity, and icteric index. Feces also were collected in epidemic 1 to test for hepatitis A virus antigen. Both anti-HAV immunoglobulin M (IgM) and total anti-HAV were assayed in sera from "healthy persons" (symptomless persons without icterus and with normal SGPT level) who were in close contact with hepatitis A patients. In epidemic 1, among 18 "healthy persons", 12 were anti-HAV IgM positive, two were immune, and four susceptibles escaped infection. In epidemic 2, among 32 "healthy children", three were anti-HAV IgM positive, five had been infected by hepatitis A virus in the past, and 24 were not infected. These results demonstrate that inapparent infections occur along with overt and subclinical infections during epidemics of hepatitis A. The proportions of inapparent, subclinical, and overt infections were, respectively, 34.3%, 45.7%, and 20% in epidemic 1, and 25%, 50%, and 25% in epidemic 2. In addition, hepatitis A virus particles were demonstrated in the feces of all infected subjects who were examined and who included all levels of clinical response. These particles were identified with immuno-electron microscopy and enzyme-linked immunoassay.

Adolescent↗
PubMed1988

Studies in monkeys of attenuated hepatitis A variants.

Three HAV variants, H2M20(35 degrees C), H2M20(35 degrees C) and H2M20K5(32 degrees C), were developed by passage in different tissue culture cells and at different temperatures. Virulence for monkeys was assessed by inoculating each of the variants into four monkeys. Weekly bleeding through 16 weeks post-inoculation was assayed for anti-HAV titers and SGPT as well as LDH5 activities. And in some monkeys liver biopsies were also studied. Seroconversion was induced in all of the inoculated monkeys. The anti-HAV titers tested at 16 weeks post-inoculation were: 40-640 with H2M20(35 degrees C), 40-160 with H2M20(32 degrees C) and 20-40 with H2M20K5(32 degrees C). These variants showed different levels of virulence/attenuation for monkeys. Variant H2M20(35 degrees C) showed no evidence of attenuation, variant H2M20(32 degrees C) retained slight virulence and variant H2M20K5(32 degrees C) showed no evidence of virulence for monkeys. Criteria are proposed for assay of HAV virulence tested in monkeys.

Alanine Transaminase↗