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Biomedical subjects

R Kato

Publications and source records attributed to R Kato.

At least 631 records · Page 35Linked to original sources
PubMed1982

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by lipoxygenase inhibitors: possible role of product(s) of lipoxygenase pathway.

Induction of epidermal ornithine decarboxylase (ODC) by a topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, was inhibited by treatment of mouse skin with phenidone (3-90 mumol/mouse), nordihydroguaiaretic acid (30 mumol/mouse) or 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755C, 30 mumol/mouse), which are well-known lipoxygenase inhibitors. Phenidone and BW 755C are also to be cyclooxygenase inhibitors. Inhibition of TPA-induced ODC by indomethacin (1.12 mumol/mouse), a selective cyclooxygenase inhibitor, was counteracted by prostaglandin E2 (PGE2) (140 nmol/mouse). This counteracting effect of PGE2 was reversed by the treatment of mice with nordihydroguaiaretic acid (30 mumol/mouse) or phenidone (30 mumol/mouse). ODC activity which was suppressed by nordihydroguaiaretic acid or phenidone at a dose of 180 mumol/mouse was not further inhibited by indomethacin (1.12 mumol/mouse). In addition, the counteracting action of PGE2 (140 nmol/mouse) was not observed in mice treated with nordihydroguaiaretic acid or phenidone at a dose of 180 mumol/mouse. Thus, the suppressive effect of nordihydroguaiaretic acid or phenidone on the ODC induction by TPA would be due to the inhibition of lipoxygenase. The above findings strongly suggest that not only cyclooxygenase product (i.e., PGE2) but also lipoxygenase product(s) are involved in the mechanism of ODC induction in mouse epidermis, and a lack of either cyclooxygenase product or lipoxygenase product(s) causes a failure of ODC induction by TPA.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1982

Involvement of alpha 1-adrenergic receptors in the inhibitory effect of catecholamines on the thyrotropin-induced release of thyroxine by the mouse thyroid.

TSH enhanced the release of T4 from the mouse thyroid incubated in vitro. Norepinephrine, a nonspecific alpha-adrenergic agonist, and methoxamine, an alpha 1-agonist, inhibited the TSH-stimulated release of T4 at 10(-4) and 10(-5) M, whereas clonidine, an alpha 2-agonist, exerted a weak inhibition. The inhibitory effect of 10(-5) M norepinephrine on the T4 release stimulated by TSH was prevented by prazosin, an alpha 1-antagonist, at concentrations higher than 10(-7) M, whereas yohimbine, an alpha 2-antagonist, exerted weak activity in antagonizing the inhibition induced by norepinephrine. Norepinephrine, methoxamine, and clonidine did not significantly reduce the cAMP accumulation stimulated by TSH in the mouse thyroid incubated in vitro. These findings in the mouse thyroid indicate that catecholamines act by way of alpha 1-adrenergic receptors to suppress TSH-stimulated release of T4 without reducing the cAMP levels stimulated by TSH in the mouse thyroid.

Animals↗
PubMed1982

Cytochrome P-450 as a determinant of sex difference of drug metabolism in the rat.

1. Recent advances in the studies of sex-related differences of drug metabolism in the rat are described. Experiments with novel substrates have provided new insights into the sex differences of drug metabolism. 2. One of each form of cytochrome P-450, P-450-male and P-450-female, from liver microsomes of male and female rats, respectively, were purified to electrophoretic homogeneity. 3. These forms of cytochrome P-450 are distinguishable from each other in their catalytic, physical and immunochemical properties. 4. The use of antibodies to the two forms of cytochrome P-450 shows that P-450-male and P-450-female, present in rat-liver microsomes, are dependent on sex hormones. 5. In addition, evidence for the involvement of multiple forms of cytochrome P-450 in the occurrence of the sex difference has been presented.

Animals↗
PubMed1982

Metabolism of tiaramide in vitro. I. Oxidative metabolism of tiaramide by human and rat liver microsomes.

1. N-Dealkylation and N-oxidation of tiaramide and of its major metabolite, TRAA, by human and rat liver microsomes were investigated. 2. With human liver microsomes, N-oxidation of tiaramide was 1.5-8.0 times faster than N-dealkylation. N-Oxidation of the metabolite, TRAA, by human liver microsomes was much slower than that of tiaramide. The high recovery of tertiary amine N-oxides in human urine after tiaramide dosing reflects the high activity of N-oxidation of tiaramide by human liver microsomes. 3. Phenobarbital treatment of rats caused an increase in the liver microsomal N-dealkylation of tiaramide in vitro, but had little effect on N-oxidation. 3-Methylcholanthrene treatment of rats caused decrease of both reactions. 4. Metyrapone added to rat liver microsomes inhibited N-dealkylation more strongly than N-oxidation. Tetrahydrofuran and 7,8-benzoflavone inhibited N-dealkylation but had little effect on N-oxidation. Addition to the microsomal incubations of antisera against NADPH-cytochrome c reductase caused marked inhibition of N-dealkylation and slight inhibition of N-oxidation.

Animals↗
PubMed1982

Alpha-2 adrenergic inhibition of intestinal secretion induced by prostaglandin E1, vasoactive intestinal peptide and dibutyryl cyclic AMP in rat jejunum.

Effects of alpha adrenergic agents on intestinal secretion induced by prostaglandin E1 (PGE1), vasoactive intestinal peptide (VIP) and dibutyryl cyclic AMP (Bt2cAMP) were investigated in rat jejunum in vivo. Oxymetazoline and clonidine were more potent than epinephrine in inhibiting the PGE1-induced secretion. Methoxamine failed to inhibit the PGE1-induced secretion even with a 100-fold higher dose than that of clonidine. A high dose (1 mumol/kg) of oxymetazoline not only inhibited the PGE1- induced secretion but also enhanced net fluid absorption. Yohimbine reversed the inhibitory effect of clonidine, whereas phenoxybenzamine did not. These antagonists per se did not produce any effects on PGE1-induced secretion. Clonidine inhibited the intestinal secretion induced by VIP or Bt2cAMP, whereas methoxamine did not. The inhibitory effect of clonidine was reversed by yohimbine. Phenoxybenzamine per se inhibited intestinal secretion induced by either VIP or Bt2cAMP. Clonidine did not produce any significant effects on PGE1- augmented cAMP levels in jejunal mucosa in vivo. These results suggest that stimulation of alpha-2 adrenoceptors in rat jejunal mucosa inhibits some mechanisms distal to cAMP generation and in turn results in the inhibition of net water intestinal secretion. These findings also raise the question of general validity of a hypothesis that alpha-2 adrenoceptors regulate cellular functions through the inhibition of adenylate cyclase activity.

Adrenergic alpha-Agonists↗
PubMed1982

Metabolism and activation of aflatoxin B1 by reconstituted cytochrome P-450 system of rat liver.

Metabolism and activation of aflatoxin B1, a potent hepatocarcinogenic and mutagenic mycotoxin of Aspergillus flavus, were investigated in the reconstituted enzyme system composed of purified NADPH-cytochrome P-450 reductase and cytochrome P-450 or P-448 of rat liver. The aflatoxin M1 formation was strictly mediated by P-448 purified from the liver microsomes of polychlorobiphenyl- and 3-methylcholanthrene-treated rats, while the aflatoxin Q1 formation, as well as the binding of DNA, were catalyzed by both P-450 and P448. Differences between the kinetic data on metabolism and activation of aflatoxin B1 obtained with the reconstituted cytochrome systems and those obtained with the microsomal and nuclear systems were discussed, and the significance of these biochemical data in the in vivo carcinogenicity of aflatoxin B1 was evaluated.

Aflatoxin B1↗
PubMed1982

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibitor.

Application of 12-O-tetradecanoylphorbol-13-acetate (TPA; 20 nmol/mouse), a tumor-promoting agent, to mouse skin results in an induction of epidermal ornithine decarboxylase (ODC; EC 4.1.1.17). Induction of ODC by TPA was inhibited by treatment of skin with indomethacin (1.12 mumol/mouse), a cyclooxygenase inhibitor, and the ODC activity suppressed by indomethacin was completely restored by concurrent application of prostaglandin E2 (PGE2) (140 nmol/mouse) as described first by Verma et al. (Cancer Res., 40: 308-315, 1980). Treatment of mice with tetracaine (20 and 100 mumol/mouse), a nonspecific phospholipase A2 inhibitor, inhibited the induction of ODC by TPA. More specific phospholipase A2 inhibitors, mepacrine (20 mumol/mouse) and p-bromophenacyl bromide (10 mumol/mouse), also inhibited the ODC induction. The TPA-induced ODC inhibited by mepacrine was not restored by the treatment of mice with PGE2. TPA-induced ODC inhibited by either mepacrine or p-bromophenacyl bromide was partially but significantly restored by treatment with arachidonic acid (1 to 40 mumol/mouse). Neither PGE2 nor arachidonic acid alone could induce the epidermal ODC. Treatment of mice with nordihydroguaiaretic acid (10 to 90 mumol/mouse), a lipoxygenase inhibitor, also inhibited the induction of ODC by TPA. These results strongly indicate that the stimulation of phospholipase A2 activity is a crucial process in inducing mouse epidermal ODC by TPA and not only cyclooxygenase product (i.e., PGE2) but also lipoxygenase product(s) are involved in the mechanism of ODC induction. Our present data also suggest that the above arachidonate metabolites are essential but not sufficient factors for the TPA-stimulated induction of ODC.

Animals↗
PubMed1982

Decrease in the activity of hepatic microsomal drug-metabolizing enzymes in tumor-bearing nude mice.

The activities of hepatic microsomal drug-metabolizing enzymes in nude mice (BALB/c-nu/nu) bearing tumors of human or nude mouse origin were studied. The content of cytochrome P-450 and the activities of cyclophosphamide oxidase, benzo[a]pyrene hydroxylase, aniline hydroxylase and benzphetamine N-demethylase were markedly decreased in tumor-bearing nude mice in accordance with previous observations in tumor-bearing rats and mice. These results indicate that decreases in the activities of hepatic microsomal drug-metabolizing enzymes are not the consequence of an immunoreactive process or cachexia.

Animals↗
PubMed1981

Adrenergic receptors and the onset of streptozotocin-induced diabetes in mice.

Treatment with yohimbine, an alpha 2-adrenergic blocker, prior to the injection of a subdiabetogenic dose of streptozotocin (STZ) produced hyperglycemia and hypoinsulinemia in mice 7 days later. Prazosin, an alpha 1-adrenergic blocker, was ineffective. The capacity of phentolamine and phenoxybenzamine to potentiate the diabetogenic effect of STZ was intermediate between that of yohimbine and prazosin. Propranolol and hexamethonium inhibited the potentiating action of yohimbine. Yohimbine enhanced the potentiating effect of isoproterenol on the STZ-induced diabetes. Acute changes in phase glucose and insulin levels induced by STZ were potentiated by yohimbine but not by prazosin. The insulin releasing ability of the pancreatic islets 7 days after STZ was all but lost in mice pretreated with yohimbine but not with prazosin. These results suggest that the beta- and alpha 2-, not alpha 1-adrenergic system which modulates insulin release from pancreatic islets influences the response to the diabetogenic action of STZ in mice.

Adrenergic alpha-Antagonists↗
PubMed1981

Acute physical dependence induced by continuous intravenous infusion of morphine or meperidine in the rat.

An intravenous infusion method is described for rapidly producing physical dependence in rats. Rats were infused with morphine or meperidine for 24 or 48 h at constant rates and the development of physical dependence was assessed by body weight loss after naloxone challenge. Naloxone challenge induced body losses that were dependent upon magnitude, rate and duration of infusion. The steady-state concentrations of morphine (4 mg/kg/h) in serum and meperidine (6 mg/kg/h) in plasma were 4 and 2.5 microgram/ml, respectively. Morphine concentration in the brain in the steady-state (40 mg/kg/h) was 0.7 micrograms 1 g and in the serum was proportional to the infusion rate. Maximum body weight loss was significantly correlated with total amount of infused morphine, but not with the steady-state concentration of the drug in the serum. These results suggest that total doses of infused morphine, not steady-state concentrations, are critical in producing body weight loss.

Animals↗