H Kitagawa

Chiba University, Tiba, Chiba, Japan

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Publications (160)191.79 Total impact

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    ABSTRACT: The concomitant administration of diazepam and imipramine hydrochloride increased desipramine concentration in rat plasma, but decreased 2-hydroxyimipramine and 2-hydroxydesipramine concentrations; the concomitant administration of oxazepam and imipramine hydrochloride decreased imipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine concentrations. Imipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2-hydroxydesipramine were increased by concomitant administration of oxazepam and imipramine hydrochloride. Concomitant administration of benzodiazepines and imipramine hydrochloride increased imipramine concentration in the brain. The effects of imipramine hydrochloride on hypothermia induced by reserpine, and on behavioral despair in rats was also studied. The concomitant administration of diazepam and imipramine hydrochloride led to a decrease in the anti-reserpine effect of imipramine hydrochloride and in the imipramine hydrochloride-induced recovery from immobility in the forced swimming test. These results are in accord with the findings on brain concentrations of imipramine and its metabolites.
    Journal of Pharmaceutical Sciences 09/2006; 77(1):56 - 63. · 3.13 Impact Factor
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    ABSTRACT: The role of cytochrome P450 (P450) in lipid peroxidation induced by NADPH or peroxide was investigated in a reconstituted system. When cumene hydroperoxide, t-butyl hydroperoxide and hydrogen peroxide were used as initiators, the rates of malondialdehyde (MDA) formation were much higher in a reconstituted system containing P450 1A1 than those observed in a reconstituted system containing P450 1A2. In contrast to peroxide-induced lipid peroxidation, P450 1A2 catalysed NADPH-induced lipid peroxidation more effectively than did P450 1A1 regardless of the presence of ADP-Fe(NO3)3. Carbon monoxide inhibited NADPH-induced formation of MDA in a reconstituted system containing P450 1A2, but not P450 1A1. In addition, superoxide dismutase (SOD) was an effective inhibitor in a NADPH-induced lipid peroxidation system catalysed by P450 1A2 but not by P450 1A1. These results suggest that a peroxide-induced reaction might proceed readily with P450 1A1, whereas P450 1A2 mainly functions in NADPH-induced lipid peroxidation via generation of an active oxygen species. It is furthermore indicated that the difference in the effect of SOD in NADPH-induced lipid peroxidation depends on the P450 used.
    Biochemical Pharmacology 08/1993; 46(1):55-60. · 4.65 Impact Factor
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    ABSTRACT: A cytochrome P450 (P450) (referred to as P450CMLa) was purified and characterized from hepatic microsomes from untreated cynomolgus monkeys (Macaca irus). The final preparation was electrophoretically homogeneous and its estimated minimum molecular mass was 49.5 kDa. The amino-terminal amino acid sequence of the protein (first 34 residues) closely resembled that of the protein encoded by the 2B6 cDNA from humans (94%). This protein was cross-reactive with antibodies raised against P450 2B1 (P450 b), P450 2B11 (P450 PBD-2), and P450GP-1, which were purified from hepatic microsomes from phenobarbital-pretreated rats, beagle dogs, and guinea pigs, respectively. Also, the antibody raised against P450CMLa was able to cross-react with P450 2B1, P450 2B11, and P450GP-1. P450CMLa was capable of catalyzing benzphetamine N-demethylation and testosterone 16 beta-hydroxylation in a reconstituted system. Anti-P450CMLa antibody inhibited the activity of testosterone 16 beta-hydroxylase but not the activities of testosterone 2 beta- and 6 beta-hydroxylases in liver microsomes from cynomolgus monkeys. The content of P450CMLa, as estimated by immunoblot analysis, was 70 pmol/mg (about 5% of total P450). The protein immunoreactive with the anti-P450CMLa antibody was also present in liver microsomes from Japanese monkeys, baboons, common marmosets, and common squirrel monkeys. In liver microsomes from common squirrel monkeys, the content of protein immunoreactive with the anti-P450CMLa antibody and the activity of testosterone 16 beta-hydroxylase were effectively increased by pretreatment with phenobarbital. The antibody against P450CMLa strongly inhibited the activity of testosterone 16 beta-hydroxylase in liver microsomes not only from untreated cynomolgus monkeys but also from phenobarbital- and pregnenolone 16 alpha-carbonitrile-pretreated common squirrel monkeys. These results indicated that the P450CMLa purified here is very similar to the forms of P450 classified into the 2B subfamily, in its amino-terminal amino acid sequence, catalytic activities, and immunochemical properties.
    Molecular Pharmacology 03/1993; 43(2):183-90. · 4.12 Impact Factor
  • K Ueno, A R Saha, T Satoh, H Kitagawa
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    ABSTRACT: Heptaminol AMP amidate (HAA), a nucleotide derivative increased the percentage of T cell surface phenotypes on peripheral blood lymphocytes (PBL) of mice primed with sheep red blood cells. The T cell surface phenotypes Thy1.2, Lyt1, L3T4 and Lyt2 increased on the PBL of HAA administered mice to 136, 145, 144 and 153%, respectively over those on the PBL of control mice.
    Research communications in chemical pathology and pharmacology 02/1991; 71(1):125-8.
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    ABSTRACT: Heptaminol AMP amidate (HAA), a nucleotide derivative, was found to elevate the intracellular cyclic AMP (cAMP) level of cultured mice spleen cells in a time- and dose-dependent manner. Theophylline and imidazole, when added to the spleen cell culture simultaneously with HAA, respectively caused a further rise and a fall of the cAMP level increased by HAA alone. When comparatively higher doses of the T cell mitogen concanavalin A (Con A) were used in the culture, Con A-induced cell proliferation was mildly inhibited in the culture of spleen cells pooled from HAA administered mice in comparison to the culture of spleen cells pooled from saline treated mice. On the other hand, when another T cell mitogen phytohemagglutinin P (PHA) was used in different concentrations in the culture, there was a trend of enhanced cell proliferation in the culture of spleen cells pooled from HAA administered mice in comparison to the responses in the culture of spleen cells pooled from saline treated mice. The present results supported the previous findings that HAA-mediated immunopotentiation was closely related with a cAMP level elevating property of HAA, and the compound also enhanced the function of helper T cells.
    The Japanese Journal of Pharmacology 04/1990; 52(3):483-8.
  • A R Saha, K Ueno, H Kitagawa, T Satoh
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    ABSTRACT: Hepataminol AMP amidate (HAA), a nucleotide derivative possessing immunopotentiating activities, inhibited the mitogen-induced proliferation of murine splenocytes in vitro at the higher concentrations. Concanavalin A-induced mitogenic response was inhibited to 65 and 15% of the control value by HAA at the concentrations of 10(-4) and 10(-3) M, respectively. HAA also inhibited phytohemagglutinin P and lipopolysaccharide-induced responses at the same concentrations. The pattern of inhibition of mitogen-induced responses by HAA at higher concentrations was found to be almost similar to that of dibutyryl cyclic AMP (DbcAMP). Both HAA and DbcAMP also inhibited the blastogenesis of spleen cells in one way mixed lymphocyte reaction.
    Research communications in chemical pathology and pharmacology 04/1990; 67(3):337-48.
  • M Kubota, K Ueno, M Yamano, H Kitagawa
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    ABSTRACT: It has been known that many antidepressant drugs which have serotonin (5-HT) antagonistic activities and 5-HT antagonists can induce the reduction of 5-HT2 receptor binding by their acute or successive administration. We investigated the effects of repeated treatment with 5-HT agonists on 5-HT2 receptors in rat cerebral cortex. We used citalopram as selective 5-HT uptake inhibitor, 5-hydroxytryptophan as 5-HT precursor, and 5-methoxy-N,N'-dimethyltryptamine as 5-HT2 agonist. The 5-HT2 receptor density was decreased by repeated treatment with these respective drugs. So it may be supposed that the reduction of 5-HT2 receptor binding is induced not only by 5-HT antagonists but also by 5-HT agonists.
    Yakubutsu, seishin, kōdō = Japanese journal of psychopharmacology 10/1989; 9(3):289-92.
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    ABSTRACT: The effects of a minor tranquilizer, zopiclone, on endocrine system in male rats were assessed to clarify the mechanisms whereby large doses of zopiclone may induce testicular damage. 1) Zopiclone had no significant effect on plasma and tissue levels of hormones of the hypophyseo-gonadal or -thyroid system in rats given 10, 100 and 250 mg/kg/day orally for 28 days. 2) Rats given zopiclone in doses of 10 and 100 mg/kg/day orally for 14 days had lowered serum levels of PGE2 and PGF2 alpha but the testicular PGF2 alpha concentration remained unchanged. Therefore, oral administration of high doses of zopiclone to rats has no evident influence on endocrine system related to male reproduction. And these findings support our previous paper that repeated dose of zopiclone cause no significant change in plasma or epididymal TS levels, nor to any change in lipid peroxidation in testicular tissues.
    Research communications in chemical pathology and pharmacology 06/1989; 64(2):255-71.
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    ABSTRACT: Heptaminol AMP amidate (HAA), a newly developed nucleotide derivative, was found to restore the immunosuppression in mice due to the induction of suppressor T (Ts) cells by concanavalin A (Con A) (50 micrograms/body). HAA also inhibited Con A-mediated in vitro induction of Ts cells. On the contrary, the administration of HAA in mice primed with keyhole lympet hemocyanin (KLH) (30 micrograms/body) caused an enhanced induction of antigen specific helper T (Th) cells. Effects of HAA on Ts and Th cells were found to be dependent on their level of induction. The administration of HAA also increased the spleen cell number and augmented the plaque forming cell response to some extent in cyclophosphamide treated mice. The present results suggested that HAA-mediated immunopotentiation was possible by a combined suppressive effect on Ts cells and enhancing effect on Th cells.
    The Japanese Journal of Pharmacology 01/1989; 48(4):417-22.
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    ABSTRACT: Dog liver cytosolic glutathione S-transferases (GSTs) were investigated to characterize their properties in comparison with rat liver transferases. Dog liver GSTs after the glutathione affinity column chromatography showed three subunit bands on SDS-polyacrylamide gel electrophoresis. These three subunits, designated as Yd1 (mol.wt 26,000), Yd2 (mol.wt 27,000) and Yd3 (mol.wt 28,000), were distinctly different from rat liver GST subunits, i.e. Ya(1) (mol.wt 26,500), Yb1(3)/Yb2(4) (mol.wt 27,500) and Yc(2) (mol.wt 28,500). Western blot analysis revealed that Yd1, Yd2 and Yd3 were immunoreacted with anti-rat GST 7-7, 1-1 and 3-3 antibodies, respectively. Four transferase activity fractions, I (pH greater than 7.63), II (pH 6.92), III (pH 5.80) and IV (pH 5.65), were obtained from affinity purified GSTs by chromatofocusing. Each fraction exhibited a characteristic substrate specificity. GST-II, III and IV were all strongly immunoreacted with anti-rat GST 7-7 antibody by immunoblotting, thus suggesting the occurrence of the heterogeneity of transferases immunologically related to rat GST subunit 7 in dog liver. Immunohistochemical examination showed that transferases immunoreacted with anti-GST 7-7 antibody have diffusely distributed throughout the lobule, while enzymes related to subunit 3 have been localized in a narrow range of cells around the central vein. These data suggest that GSTs immunologically associated with rat transferase subunit 7 may be major forms in dog liver.
    Biochemical Pharmacology 01/1989; 37(24):4713-8. · 4.65 Impact Factor
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    ABSTRACT: This is the first report for the hepatic lipid peroxide lowering effect of spermine in vivo. The influence of administration of polyamines on hepatic lipid peroxide level has been investigated by using normal or carbon tetrachloride (CCl4)-treated rats. Spermine was found to lower the hepatic lipid peroxide level most efficiently among polyamines used in CCl4-treated rats. In addition, the extent of liver enlargement caused by CCl4 treatment was reduced by spermine administration. Lipid peroxide lowering effect of spermine was also observed in normal rats. Hepatic spermine content was significantly increased in both normal and CCl4-treated rats after administration of spermine. Clear inverse relationship between the content of lipid peroxide and the concentration of spermine was observed. In reconstituted system containing NADPH-cytochrome P-450 reductase and extracted hepatic microsomal lipid, spermine inhibited the NADPH-dependent lipid peroxidation effectively at the concentration of 0.1 mM. From these results, we concluded that spermine exerted an inhibitory effect of lipid peroxidation in vivo as well as in vitro.
    Research communications in chemical pathology and pharmacology 12/1988; 62(2):235-49.
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    ABSTRACT: The effects of eicosapentaenoic acid (EPA) on the humoral immune response in fat free diet-fed (FF) mice were studied. The lowered anti-SRBC PFC activity of ICR male FF mice was restored in a dose-dependent manner when EPA was administered orally at doses of 60-360 mg/kg/day for 20 days. In in vitro experiments, EPA similarly enhanced anti-SRBC PFC activity but did not affect the response against lipopolysaccharide. Furthermore, EPA did not cause any substantial effect on T suppressor cell activity induced by Concanavalin A in vitro. On the other hand, T helper cell activity induced by keyhole limpet hemocyanin was augmented. From these results, it is suggestive that EPA caused immunopotentiation to FF mice at least partially by an enhancement of T helper cell activities.
    Research communications in chemical pathology and pharmacology 11/1988; 62(1):49-66.
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    ABSTRACT: NADPH-cytochrome P-450 reductase was purified to 30.8 units/mg from monkey liver microsomes. The purified reductase showed one major protein band (78,000) and two minor ones (58,000 and 20,000) on analysis by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Monkey, rat, and guinea pig reductases were not immunochemically identical to each other judged from Ouchterlony double diffusion analysis and immunotitration with regard to NADPH-cytochrome c reductase activity.
    Biochemistry international 09/1988; 17(2):249-56.
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    ABSTRACT: The effects of nitroimidazoles as radiosensitizers on intracellular glutathione (GSH) level were investigated in rat isolated hepatocytes. Dinitroimidazoles have lowered almost completely GSH level during the incubation for 30 min under oxic (95% O2+5% CO2) condition, while mononitroimidazoles had scarcely affected. In the case of hypoxic (95% N2+5% CO2) condition, however, 2-nitroimidazoles, not 4-nitroimidazoles, as well as 2,4- and 4,5-dinitroimidazoles have caused the significant depletion of GSH. This suggests that nitro group in the 2-position of imidazoles may be responsible for the GSH depletion under hypoxia. Especially, 2-nitroimidazole-1-acetohydroxamic acid (KIH-801) was found to be the most potent GSH depletor only under hypoxic, not oxic conditions, and might be useful for the new hypoxic cell radiosensitizer instead of misonidazole.
    Biochemistry international 08/1988; 17(1):155-62.
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    ABSTRACT: Heptaminol AMP amidate (HAA), a newly developed derivative of 5'-AMP, was found to potentiate the in vitro primary humoral immune response against T cell-dependent antigen, sheep red blood cells, when HAA was present in the early phase of spleen cell culture. Such a potentiating effect was not found against T cell-independent antigens such as lipopolysaccharide (LPS), trinitrophenylated (TNP)-LPS and TNP-Ficoll. The pattern of HAA-mediated immunopotentiation was similar to that of dibutyryl cyclic AMP. When HAA was added to the culture simultaneously with theophylline and imidazole, the immunopotentiating effect of HAA was further augmented and suppressed, respectively. The present results suggested that HAA-mediated immunopotentiation might be in some way related to the intracellular level of cyclic nucleotides in the early phase of culture.
    The Japanese Journal of Pharmacology 06/1988; 47(1):63-9.
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    ABSTRACT: The effect of carbon tetrachloride (CCl4) treatment on plasma and liver cytosolic glutathione S-transferase (GST) activities was investigated in rats. CCl4 was intraperitoneally administered at a dose of 0.5 ml/kg. The elevation of plasma GST activity paralleled the increase of plasma glutamate pyruvate transaminase activity after the administration of CCl4. Liver cytosolic GST activities were significantly decreased by CCl4 treatment. To establish the relationship of plasma GST with liver cytosolic isozymes, Western blot analysis using antibodies against cytosolic GST 1-2 and 3-4 was performed. The Western blots showed the existence of GST 1-2 and 3-4 in plasma at 24 hr after CCl4 treatment. The data thus strongly suggest that cytosolic GSTs are lost from the liver to plasma as a consequence of liver damage. The Western blot analysis of plasma GST may be useful for monitoring liver damage.
    The Japanese Journal of Pharmacology 04/1988; 46(3):211-6.
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    ABSTRACT: The in vitro effect of trichosanic acid (TCA; C18:3, omega-5), a major component of Trichosanthes japonica, on platelet aggregation and arachidonic acid (AA) metabolism in human platelets was studied. TCA dose-dependently suppressed platelet aggregation of platelet rich plasma and washed platelets. TCA decreased collagen (50 micrograms/ml)-stimulated production of thromboxane B2 (TXB2) and 12-hydroxyhepta-decatrienoic acid (HHT) in a dose-dependent manner, while that of 12-hydroxyeicosatetraenoic acid (12-HETE) was rather enhanced. The conversion of exogenously added [14C]AA to [14C]TXB2 and [14C]HHT in washed platelets was dose-dependently reduced by the addition of TCA, while that to [14C]12-HETE was increased. Similar observations were obtained when linolenic acid (LNA; C18:3, omega-3) was used. These results suggest that TCA may decrease TXA2 formation in platelets, probably due to the inhibition of cyclooxygenase pathway, and thereby reduce platelet aggregation.
    Prostaglandins Leukotrienes and Essential Fatty Acids 03/1988; 31(2):65-72. · 1.98 Impact Factor
  • K Ueno, H Masumura, H Kawamoto, H Kitagawa
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    ABSTRACT: The effects of oral administration of ketoprofen, naproxen, flurbiprofen (1.0 mg/kg), indomethacin (1.0 and 3.0 mg/kg), and acetylsalicylic acid (100 mg/kg) on release of prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E (PGE) from isolated pregnant rabbit uterus were studied comparatively. Ketoprofen, indomethacin, flurbiprofen, naproxen and acetylsalicylic acid reduced the release of PGF2 alpha and PGE from the isolated rabbit uterus. The inhibitory effect was most profound with flurbiprofen, followed, in order, by naproxen, ketoprofen, indomethacin and acetylsalicylic acid. A comparative study with intramuscular ketoprofen (0.1, 1.0 and 3.0 mg/kg) was also carried out. The inhibitory effect of ketoprofen on uterine PGF2 alpha and PGE release with intramuscular route was about 10 times more profound than that with oral route.
    Research communications in chemical pathology and pharmacology 02/1988; 59(1):141-4.
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    ABSTRACT: The concomitant administration of diazepam and imipramine hydrochloride increased desipramine concentration in rat plasma, but decreased 2-hydroxyimipramine and 2-hydroxydesipramine concentrations; the concomitant administration of oxazepam and imipramine hydrochloride decreased imipramine, 2-hydroxyimipramine, and 2-hydroxydesipramine concentrations. Imipramine plasma protein binding was unaltered in all cases. Liver concentrations of imipramine and 2-hydroxydesipramine were increased by concomitant administration of oxazepam and imipramine hydrochloride. Concomitant administration of benzodiazepines and imipramine hydrochloride increased imipramine concentration in the brain. The effects of imipramine hydrochloride on hypothermia induced by reserpine, and on behavioral despair in rats was also studied. The concomitant administration of diazepam and imipramine hydrochloride led to a decrease in the anti-reserpine effect of imipramine hydrochloride and in the imipramine hydrochloride-induced recovery from immobility in the forced swimming test. These results are in accord with the findings on brain concentrations of imipramine and its metabolites.
    Journal of Pharmaceutical Sciences 02/1988; 77(1):56-63. · 3.01 Impact Factor
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    ABSTRACT: The effects of daily oral administration of imipramine (IM) hydrochloride (50 mg/kg) and/or oxazepam (OZ, 20 mg/kg) or diazepam (DZ, 5 mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the activities of drug metabolizing enzyme systems and steady state plasma levels of IM, desmethylimipramine (DIM), DZ, desmethyl-diazepam (DDZ) and OZ were investigated in rats during a 15-day period. In addition, the effect of a single intravenous administration of IM hydrochloride (5 mg/kg), DZ (0.5 mg/kg) and OZ (2 mg/kg) on plasma concentration-time profiles of IM, DIM, DZ, DDZ and OZ was investigated in rats given the same drug treatments by the oral route for 14 days. The group treated with IM hydrochloride plus OZ group showed a great increase in drug-metabolizing enzyme activities, but the difference for the group given IM hydrochloride was not statistically significant. The steady-state plasma levels of DZ after oral administration for 15 days suggested that the group given IM hydrochloride plus DZ did show accumulated DZ. In terms of the area under the concentration-time curve of IM, DZ and OZ after intravenous administration of IM hydrochloride, DZ and OZ, there were significant differences between each of the mono-treatment groups and the IM hydrochloride plus DZ or OZ treatment groups. In conclusion, we have found that the drug interaction for IM hydrochloride by OZ is markedly lower than that by DZ.
    Folia Pharmacologica Japonica 02/1988; 91(1):41-53.