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Biomedical subjects

K Chiba

Publications and source records attributed to K Chiba.

At least 379 records · Page 21Linked to original sources
PubMed1985

Metabolism of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by liver homogenate fractions.

The metabolic fate of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been examined in rat and rabbit liver mitochondrial and rabbit liver microsomal preparations. The mitochondrial preparations rapidly oxidized MPTP, in a pargyline-sensitive reaction, to a polar material that was shown to contain the 1-methyl-4-phenylpyridinium species as the principal product. NADPH-supplemented microsomal preparations converted MPTP to two principal products: 4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. Carbon monoxide and SKF 525A selectively inhibited the oxidation of MPTP to the nor compound, indicating that this N-demethylation reaction is cytochrome P-450 catalyzed. Attempts to trap possible unstable iminium metabolites of MPTP in microsomal incubation mixtures with sodium cyanide led to the isolation of a monocyano adduct that proved to be the N-cyanomethyl derivative. Thus, hepatic mitochondrial and microsomal enzyme systems catalyze the oxidation of MPTP by different pathways, the former leading to the generation of species that may possess neurotoxic properties.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is biotransformed by brain monoamine oxidase (MAO) to an unstable dihydropyridinium intermediate that reacts with cyanide ion to form an alpha-cyano-tetrahydropyridine adduct and, in the absence of cyanide ion, undergoes disproportionation to the 1-methyl-4-phenylpyridinium species MPP+ and MPTP. Comparison of the HPLC retention times, diode array UV, and chemical ion mass spectral characteristics of these products with those of synthetic standards led us to propose the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+ and 6-cyano-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as tentative structure assignments for the dihydropyridinium metabolite and the cyano adduct, respectively. Results presented in this paper confirm the first assignment and establish that, although the proposed 6-cyano adduct is initially formed, the product that was isolated from the mitochondrial incubation mixtures of MPTP and sodium cyanide actually is the isomeric 2-cyano-1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine. On the basis of the selective incorporation of deuterium into these products, we provide rational mechanistic interpretations of the disproportionation reaction and the rearrangement of the cyano adducts. These results establish that the MAO-catalyzed bioactivation of MPTP leads to the formation of a variety of reactive molecules that are potentially cytotoxic to nigrostriatal cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Comparison of food constituents in the diet of female agricultural workers in Japan with high and low concentrations of high density lipoprotein in their sera.

Over 300 female farmers from 18 regions in various parts of Japan were examined for high density lipoprotein cholesterol (HDL) in the serum. Based on the HDL levels, three examinees with the highest HDL and another three with the lowest HDL were selected from each region to form the high HDL group (high group, 54 subjects) and the low HDL group (low group, 54 subjects), respectively, so that any geographical effects on HDL could be excluded. The 108 subjects were examined for serum lipid biochemistry, anthropometry, and nutrient intake (by collection and analyses of 24-hour duplicates of the diet). While the HDL level in the high group (64.8 +/- 11.2 mg/100 ml, mean +/- SD) was significantly (p less than 0.01) higher than in the low group (31.4 +/- 5.6 mg/100 ml), the low group had a higher serum triglyceride level and was more obese than the high group. Nutritional analyses of the diets taken by each group member revealed that the diets of both groups were typically Japanese (ie, low calorie intake at ca 2000 kcal/day, higher dependency on carbohydrate, equal amounts of protein from animals and vegetables, and large fish intake) and essentially similar (p less than 0.05) in nutritional constituents, such as total energy, carbohydrate, fibre, saturated/unsaturated fatty acid ratio or sodium chloride, except that members of the high group took significantly (p less than 0.01 approximately 0.05) more protein and fat (thus more of both saturated and unsaturated fatty acids). None of the nutritional items studied appeared to explain the different HDL levels in the two groups.

Adult↗
PubMed1985

Stimulated rat T cell-derived inhibitory factor for cellular DNA synthesis (STIF). II. Kinetics of the production and characterization of the producer.

Kinetics of the production of a stimulated T cell-derived inhibitory factor for cellular DNA synthesis (STIF) (1) from Con A-stimulated SD rat spleen cells, and the cells involved in the production of the factor, were examined comparatively with those of interleukin 2 (IL 2) and interferon (IFN). STIF activity in the culture supernatants reached a plateau 24 hr after the culture, and the plateau level was maintained during an additional culture for 72 hr. Characterization of the cells involved in STIF production by means of negative selection of unfractionated or nylon-fractionated spleen cells with anti-rat T cell serum or monoclonal antibodies plus complement revealed that the cells are nylon-nonadherent T cells bearing a suppressor T cell marker. The nylon-nonadherent T cell population did not require additional macrophages for STIF production. In vivo pretreatment of rats with cyclophosphamide (25 to 100 mg/kg) reduced or abolished the production of STIF from the Con A-stimulated spleen cells of the rats. The STIF production from Con A-stimulated spleen cells was inhibited by the addition of indomethacin at 10 ng/ml, indicating a regulatory role of prostaglandin(s) in STIF production. The above characteristics distinguish a T cell subset for STIF production from those for IL 2 and IFN production.

Animals↗
PubMed1985

Stimulated rat T cell-derived inhibitory factor for cellular DNA synthesis (STIF). III. Effect on cell proliferation and immune responses.

Stimulated T cell-derived inhibitory factor for cellular DNA synthesis (STIF), a lymphokine produced from concanavalin A (Con A)-stimulated rat suppressor T cells, was examined for its inhibitory effect on various cultured cells and on in vitro immune reactions. STIF could inhibit the DNA synthesis of a variety of normal and neoplastic cells from rats, mice, and humans in a dose-dependent fashion. Kinetics studies revealed that STIF selectively inhibited cellular DNA synthesis after incubation for 12 hr, but after 36 hr, it also inhibited RNA and protein syntheses. The inhibited cellular DNA synthesis by 12-hr incubation with STIF was recovered after culturing the cells in STIF-free medium. The inhibitory effect of STIF on the DNA synthesis was not blocked by addition of a sugar (alpha-methyl-D-mannoside, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, L-fucose, or L-rhamnose) in culture, as determined by using rat bone marrow cells. STIF inhibited proliferative responses of rat lymphocytes to T cell mitogens, Con A and phytohemagglutinin, and a B cell mitogen, lipopolysaccharide, as well as IL 2-dependent growth of cloned T572 cells. It could also inhibit both blastogenesis and cytotoxic T cell generation in allogeneic mixed lymphocyte reaction. The release of IL 2 from Con A-stimulated T cells was also inhibited by the added STIF in culture, as demonstrated from the finding that IL 2 activity was not detected in the supernatants even after an anion-exchange column chromatography. These results indicate that STIF could inhibit cellular DNA synthesis in a species-unrestricted manner and thus inhibits the proliferation of various normal and neoplastic cells, and that it could also inhibit lectin- or IL 2-dependent T cell proliferation as well as IL 2 production from T cells in in vitro immune reactions.

Animals↗
PubMed1985

Stimulated rat T cell-derived inhibitory factor for cellular DNA synthesis (STIF). I. Isolation and characterization.

A lymphokine inhibitory for cellular DNA synthesis (termed STIF) was isolated from the culture supernatants of concanavalin A (Con A)-stimulated SD rat spleen cells. STIF inhibited the DNA synthesis of mouse bone marrow cells as well as mouse leukemia cells. STIF has an apparent m.w. of 45,000 to 50,000 and is separable from IL 2, m.w. 20,000 to 25,000, by Sephacryl S-200 gel filtration, but not from immune interferon (IFN) having the same m.w. as STIF. Con A-Sepharose chromatography of the fraction containing STIF and IFN could separate these lymphokines into Con A-unbound and Con A-bound fractions, respectively. Further fractionation of the STIF fraction by DEAE-Sephadex A-50 or Mono Q-FPLC anion exchange chromatography indicated that the STIF fraction contained two components of STIF activity, both showing the same pI value (5.1 to 5.6) on flat-bed isoelectric focusing. STIF was characterized as a sugar-free lymphokine of trypsin-sensitive protein nature.

Absorption↗
PubMed1984

Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.

The neurotoxic chemical MPTP (1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine) is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min. The major metabolite has been identified as the 1-methyl-4- phenylpyridinium species. This biotransformation process is blocked by 10(-7) M deprenyl and pargyline. MPTP itself inhibited the metabolism of benzylamine by brain mitochondrial fractions. These results are discussed in terms of possible bioactivation mechanisms that may be associated with the neurodegenerative properties of MPTP .

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Pharmacokinetics of nicorandil, a new coronary vasodilator, in dogs.

The kinetic disposition of nicorandil, N-[2-( nitroxy )ethyl]-3- pyridinecarboxamide (1), and its main metabolic product, N-[2-(hydroxy)-ethyl]-3- pyridinecarboxamide (II), was studied after administering intravenous and oral doses (2.5 mg/kg) of nicorandil to the same beagle dogs. The plasma concentrations were measured using a high-performance liquid chromatographic method. The pharmacokinetic data derived from intravenous administration of nicorandil were: t1/2, 0.73 plus/minus 0.11 h; Vdarea , 0.67 plus/minus 0.04 L/kg; and total plasma clearance, 13.50 plus/minus 1.05 mL/min/kg. After oral administration, nicorandil was rapidly absorbed (tmax, 0.58 plus/minus 0.11 h). The oral bioavailability was calculated as 0.72 plus/minus 0.07. The metabolic formation of the corresponding alcohol after intravenous and oral administration of the parent compound appeared to occur quite efficiently, and its elimination half-life (3.09 plus/minus 0.25 and 3.69 plus/minus 0.88 h after intravenous and oral administration of nicorandil, respectively) was longer than that of the parent compound. Since the dose employed in this study was much higher than the expected therapeutic doses, whether such a good bioavailability after a lower dose of the drug would be obtained in humans remains unanswered.

Administration, Oral↗
PubMed1984

Antipyrine clearance in patients with Gilbert's syndrome.

The pharmacokinetic parameters of antipyrine (AP) were examined in 45 normal healthy subjects (18 heavy smokers, 5 mild smokers, and 22 nonsmokers) and in 12 patients with Gilbert's syndrome (GS), amongst whom 2 mild and 1 heavy smokers were included. Heavy smokers were defined as persons smoking more than 20 cigarettes/day and mild smokers as those smoking less than 10 cigarettes/day. Significant differences (unpaired Student's t-test) in the elimination t1/2 of AP among the study groups and in its total plasma clearance (CL) were observed without any change in the apparent volume of distribution. The individual CL values varied within the same study groups, but the mean +/- SD (0.026 +/- 0.004 l/h/kg) in the GS patients did not significantly differ from that in normal nonsmokers (0.025 +/- 0.006 l/h/kg) or in normal mild smokers (0.028 +/- 0.001 l/h/kg). When the 3 patients with GS who smoked were excluded, the mean CL of the group (0.025 l/h/kg) was again comparable to that of the normal nonsmokers and mild smokers. The mean (+/- SD) CL in normal heavy smokers (0.040 +/- 0.012 l/h/kg) was significantly greater than in normal mild smokers (p less than 0.05), in normal nonsmokers (p less than 0.001) and in patients with GS (p less than 0.001). The results suggest that drug oxidation capacity estimated from the total plasma CL of AP appears unimpaired in GS.

Adult↗