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Biomedical subjects

R Kato

Publications and source records attributed to R Kato.

At least 649 records · Page 36Linked to original sources
PubMed1981

Metabolic activation of glutamic acid pyrolysis products, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-amino-dipyrido[1,2-a:3',2'-d]imidazole, by purified cytochrome P-450.

Metabolic activation by cytochrome P-450 of glutamic acid pyrolysis products, 2-amino-6-methyldipyrido(1,2-a:3',2'-d)imidazole (Glu-P-1) and 2-amino-dipyrido(1,2,-a:3',2'-d)imidazole (Glu-P-2), to mutagenic metabolites was studied using Salmonella typhimurium TA98 as a tester strain. Cytochrome P-450, NADPH-cytochrome P-450 reductase and NADPH were essential requirements for the activation of these compounds. Of the four forms of cytochrome P-450 examined, polychlorinated biphenyls (PCB) P-448 and 3-methylcholanthrene (MC) P-448 purified from liver microsomes of rats treated with a PCB mixture and MC, respectively, showed high activity in the activation of both Glu-P-1 and Glu-P-2. The presence of three metabolites from Glu-P-1 or Glu-P-2 was demonstrated by high performance liquid chromatographic (HPLC) analysis. Among the metabolites of Glu-P-1, two metabolites were mutagenic without any further enzymatic activation. In accordance with the results of a mutation assay, PCB P-448 also exhibited higher activity to form the major mutagenic metabolite of Glu-P-1. The major active metabolite of Glu-P-1 was characterized as N-hydroxy-Glu-P-1 by chemical analysis using oxidizing and reducing reagents and by mass spectrometry.

Animals↗
PubMed1981

Metabolic activation of a tryptophan pyrolysis product, 3-amino-1-methyl-5H-pyrido[4,3-b]indole(TRP-P-2) by isolated rat liver nuclei.

The metabolic activation of a tryptophan pyrolysis product, 3-amino-1-methyl-5H-pyrido[4,3-b]indole(Trp-P-2), by rat liver nuclei was studied. Nuclei from the livers of rats treated with polychlorinated biphenyl (PCB) or 3-methylcholanthrene (MC) showed high mutagenic activity with Trp-P-2 in the Ames test, but activities with nuclei of untreated or phenobarbital (PB)-treated rat livers were quite low. The formation of N-hydroxy-Trp-P-2 by nuclei of PCB- or MC-treated rat livers was greater than that by nuclei of untreated or PB-treated rat livers. Similar results were observed with microsomes, which suggests that Trp-P-2 is metabolized by the same type of monoxygenase system in nuclei as in microsomes.

Animals↗
PubMed1981

Partial agonistic action of morphine in the rat vas deferens.

Effects of morphine on the force of contraction of rat vas deferens were investigated. Morphine and beta-endorphin decreased the electrically evoked twitch tension, in a dose dependent manner. The inhibitory effect of morphine, however, was much weaker than that of beta-endorphin. These effects of both morphine and beta-endorphin were completely antagonized by naloxone. In the presence of 30 microM morphine, the dose-response curve of beta-endorphin shifted to the right by about 10-fold. Moreover, morphine partly reversed the contraction depressed by 0.3 microM beta-endorphin, in a dose dependent manner. These findings suggest that morphine acts as a partial agonist on the rat vas deferens. Marked tolerance to beta-endorphin and change in the antagonist potency of morphine were not observed in the vas deferens isolated from morphine-dependent rats.

Animals↗
PubMed1981

Postsynaptic alpha-2 adrenergic receptors in isolated rat islets of Langerhans: inhibition of insulin release and cyclic 3':5'-adenosine monophosphate accumulation.

Effects of various alpha adrenergic agents on insulin release and cyclic 3':5'-adenosine monophosphate (cAMP) accumulation in pancreatic islets were investigated. Clonidine, epinephrine, alpha-methylnorepinephrine and norepinephrine were most potent and methoxamine and phenylephrine least potent in inhibiting the glucose-stimulated insulin release. Yohimbine and phentolamine were the most effective and prazosin was the least effective in antagonizing the epinephrine-inhibited insulin release. Clonidine markedly inhibited the glucagon-stimulated cAMP accumulation, whereas methoxamine showed weak inhibition. Yohimbine markedly increased cAMP accumulation in the presence of epinephrine, whereas prazosin showed little effect. The effects of alpha adrenergic agents on rabbit aorta contraction were also examined for comparison with alpha adrenergic receptors in pancreatic islets. In the aorta, the order of agonist potency was norepinephrine greater than phenylephrine greater than epinephrine greater than methoxamine greater than alpha-methylnorepinephrine and that of antagonist potency was prazosin greater than WB-4101 greater than phentolamine greater than dihydroergotamine greater than phenoxybenzamine greater than yohimbine. These orders of potencies were markedly different from those in pancreatic islets. These results clearly demonstrate that the alpha adrenergic receptors in rat pancreatic islets are different from those on rabbit aorta (alpha-1) and are typical postsynaptic alpha-2 adrenergic receptors.

Adrenergic alpha-Agonists↗
PubMed1981

Species difference in N-hydroxylation of a tryptophan pyrolysis product in relation to mutagenic activation.

Metabolic activation of a tryptophan pyrolysate, 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), in liver microsomes from rats, mice, hamsters, guinea pigs, and rabbits was studied to know whether N-hydroxylation is a common obligatory step for mutagenic activation of Trp-P-2. Among hepatic microsomes obtained from untreated animals, the highest activity of Trp-P-2 N-hydroxylase was observed in microsomes from hamsters, followed by those from guinea pigs, mice, and rabbits. In rats, the activity was low, and there was no appreciable difference between the sexes. The activity of Trp-P-2 N-hydroxylase in microsomes was increased by pretreating the animals with a polychlorinated biphenyl mixture. The induction was most profound in rats, and the activity was enhanced 257-fold, as compared to that of untreated animals. The activity was also enhanced in microsomes from polychlorinated biphenyl mixture-treated rabbits, mice, and hamsters, while the activity was increased only slightly in guinea pigs and was thereby lowest among microsomes from the polychlorinated biphenyl mixture-treated animals. In bacterial mutagenesis test systems using Salmonella typhimurium TA 98, the number of revertants induced by Trp-P-2 was increased in parallel with the microsomal ability of the N-hydroxylation. These results indicate that in all species examined N-hydroxylation is an essential metabolic step for mutagenic activation of Trp-P-2.

Animals↗
PubMed1981

Evidence for the involvement of N-hydroxylation of 3-amino-1-methyl-5H-pyrido[4,3-b]indole by cytochrome P-450 in the covalent binding to DNA.

The involvement of N-hydroxylation of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) by cytochrome P-450 in the formation of covalent binding of Trp-P-2 to DNA, the induction of his+ revertant in the Ames test, and the formation of the active metabolite were confirmed. Among four cytochrome P-450 preparations, PCB-P-448 and MC-P-448 purified from liver microsomes of polychlorinated biphenyl (PCB)- and 3-methylcholanthrene-treated rats, respectively, showed higher activities for induction of mutation by Trp-P-2 than did the other two preparations, PCB-P-450 and PB-P-450 purified from PCB-and phenobarbital (PB)-treated rats, respectively. PCB-P-448 was more active than was PB-P-450 in metabolizing Trp-P-2 to N-hydroxylated Trp-P-2 (N-hydroxy-Trp-P-2). Cytochrome P-450 with higher capacity to form the N-hydroxylated metabolite induced a larger number of his+ revertants. Larger amounts of [1-14C]Trp-P-2 bound covalently to DNA were also seen when PCB-P-448 was incubated with calf thymus DNA and reduced nicotinamide adenine dinucleotide phosphate than with PCB-P-450 and PB-P-450. The direct binding of N-[ring-3H]hydroxy-Trp-P-2 isolated by high-performance liquid chromatography to calf thymus DNA was also demonstrated. These results indicate that N-hydroxylation of Trp-P-2 is an obligatory step for the covalent binding to DNA and mutagenesis of Trp-P-2. Based on these results, we propose that N-hydroxy-Trp-P-2 produced by cytochrome P-450 is important in the exertion of the mutagenicity of Trp-P-2 as it binds to DNA.

Animals↗
PubMed1980

Regulation of plasma insulin level by alpha 2-adrenergic receptors.

Phentolamine, yohimbine or dihydroergotamine markedly increased plasma immunoreactive insulin (IRI) and inhibited epinephrine-induced hyperglycemia in fasted mice. On the other hand, phenoxybenzamine or prazosin only slightly increased plasma IRI and enhanced epinephrine-induced hyperglycemia. These results indicate that there is a distinct difference in the effects of alpha-adrenergic blockers on the plasma IRI and glucose levels, and that alpha-adrenergic receptors responsible for the plasma IRI level resemble alpha 2-adrenergic receptors more closely.

Adrenergic alpha-Agonists↗
PubMed1980

Mechanism of chlorpromazine action on plasma glucose and cyclic AMP levels.

The s.c. administration of chlorpromazine (CPZ) caused an elevation of plasma glucose and cyclic AMP levels in fed intact mice, but not in fed adrenalectomized mice. The pretreatment with reserpine partially blocked the elevation of plasma glucose and cyclic AMP. The pretreatment with 6-hydroxydopamine or alpha-methyl-p-tyrosine failed to inhibit the increase of plasma glucose and cyclic AMP induced by CPZ. These findings suggest that CPZ acts on the central nervous system and increases plasma glucose and cyclic AMP through epinephrine release from the adrenal medulla. The elevations of plasma glucose and cyclic AMP induced by epinephrine were enhanced by CPZ. CPZ increased plasma glucose and cyclic AMP significantly at high room temperatures (28 and 33 degrees C) at which CPZ did not decrease body temperature. The mechanism of CPZ action is discussed in relation to the increase in the plasma glucose and cyclic AMP levels.

Adrenal Glands↗
PubMed1980

Alpha 2-adrenoceptors modulating insulin release from isolated pancreatic islets.

Using rat isolated pancreatic islets, we investigated the effects of various alpha-adrenoceptor blocking agents on adrenaline-induced inhibition of glucose-stimulated insulin release. Yohimbine was about 100 times more potent than prazosin in antagonizing the inhibitory effect of adrenaline. At concentrations of 10 micro M, phentolamine was about as effective as an antagonist as yohimbine, whereas dihydroergotamine, WB-4101 and phenoxybenzamine were less effective and prazosin produced very little antagonism. These results strongly suggest that post-synaptic alpha 2-adrenoceptors modulate insulin release from pancreatic islets.

Animals↗