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Biomedical subjects

H Kitagawa

Publications and source records attributed to H Kitagawa.

At least 19 recordsLinked to original sources
PubMed1979

The involvement of cytochrome P-488 and P-450 in NADH-dependent O-demethylation of p-nitroanisole in rat liver microsomes.

These studies have shown that addition of p-nitroanisole to a reaction mixture containing rat liver microsomes resulted in an increase the reoxidation rate of NADH-reduced cytochrome b5. Fortification of rat liver microsomes with partially purified cytochrome b5 produces an increase in both NADPH-dependent and NADH-dependent p-nitroanisole O-demethylation activity. Antiserum to cytochrome P-450 isolated from phenobarbital-treated rat liver microsomes inhibited the NADH-dependent O-demethylation activity as well as the NADPH-dependent O-demethylation activity seen in rat liver microsomes. Addition of either purified cytochrome P-450 or cytochrome P-448 to an incubation mixture containing phenobarbital-treated rat liver microsomes enhanced the NADH-dependent p-nitroanisole O-demethylation activity. These results suggest that NADH-dependent and, in part, NADPH-dependent O-demethylations are catalyzed by cytochrome P-448 and cytochrome P-450 receiving electrons from cytochrome b5.

Animals↗
PubMed1979

Stimulation of microsomal drug oxidation activities by incorporation into microsomes of purified NADPH-cytochrome c (P-450) reductase.

The effects of addition of purified NADPH-cytochrome c (P-450) reductase on microsomal activities of aniline hydroxylation, p-phenetidine O-deethylation and ethylmorphine and aminopyrine N-demethylations were investigated utilizing microsomes from untreated, phenobarbital-treated and 3-methylcholanthrene-treated rats. The purified reductase was incorporated into microsomes. The drug oxidation activities were increased by the fortification of microsomes with the reductase while the extent of increase in the activities varied with the substrate and microsomes employed. The most pronounced enhancement was seen in p-phenetidine O-deethylation, followed by aniline hydroxylation and aminopyrine and ethylmorphine N-demethylations. The enhancement was more remarkable in microsomes from rats treated with 3-methylcholanthrene or phenobarbital. alpha-Naphthoflavone inhibited p-phenetidine O-deethylation activity markedly when the reductase was incorporated into microsomes, indicating that a larger amount of a species of cytochrome P-450 sensitive to the inhibitor was capable of participating in the oxidation of this substrate in the presence of the added reductase. One of the two Km values seen with higher concentrations of aniline or aminopyrine was altered by the fortification of microsomes with the purified NADPH cytochrome c (P-450) reductase. From these results, we propose that NADPH-cytochrome c (P-450) reductase transfers electrons to the selected one or two of multiple species of cytochrome P-450 more preferentially depending upon the substrate and the concentration of the substrate in microsomal membranes.

Animals↗
PubMed1979

Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo [4,3-alpha] [1,4] benzodiazepine, triazolam, a new central depressant. I. Absorption, distribution and excretion in rats, dogs and monkeys.

1. Peak radioactivity in the blood was reached at 30 min after i.p. and 1 h after oral dosing of [14C]triazolam to rats. In dogs, peak blood level was observed at 30 min after oral dosing. 2. Daily dosing of triazolam to male rats for 21 days caused a gradual increase in blood level, with peak at 1 h after dosing. 3. The rate of binding of triazolam plus its metabolites to plasma protein of rats was about 30% at 15 min and 6 h. 4. In rats, the majority of the activity of the intra-intestinally administered [14C]triazolam was found in the small intestines in 6 h. 5. About 58% of the oral dose and 77% of the i.p. dose were recovered in the bile of rats in 48 h after dosing. When the bile from one rat was introduced into the duodenum of a second rat, approximately 37% was recovered in the bile of the second animal in 24 h. 6. In male rats, high radioactivity was seen in the liver, kidneys, adrenals and heart, and low in the CNS. By 96 h after dosing, radioactivity in the liver, blood and kidneys was very low, and was undetectable in other tissues and organs. Radioactivity levels in tissues after daily dosing for 7, 14 and 21 days did not differ appreciably from single administration. 7. In monkeys, activity was high in the liver, kidneys and skin following oral administration and low in the CNS. 8. After oral administration of [14C]triazolam to pregnant rats, the activity in the uterus and placenta was higher than that in the maternal blood. The activity in the foetus was low. 9. In rats given [14C]triazolam orally or i.p., 85% and 12% of the oral dose, and 82% and 14% of the i.p. dose were recovered in the faeces and urine, respectively, in 96 h. The rate of cumulative faecal and urinary excretion after repeated dosing was similar to the single dosing with 80% and 14% of the activity recovered, respectively, in faeces and urine in 6 days. In dogs, 50% of the oral dose was found in the faeces and 40% in the urine. 10. Radioactivity in the milk of rats was maximal at 4 h after oral dosing. It declined to 34% of the peak level 48 h later.

Animals↗
PubMed1979

Metabolism of 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo [4,3-alpha] [1,4]benzodiazepine, triazolam, a new central depressant. II. Identification and determination of metabolites in rats and dogs.

1. Eight metabolites of triazolam have been identified, namely, triazolam, dichlorotriazolobenzophenone (DCTB), 1'-hydroxytriazolam, dichloro-alpha-hydroxytriazolobenzophenone (1'-hydroxy-DCTB), Ar-hydroxytriazolam, 4-hydroxytriazolam, Ar-1'-dihydroxytriazolam and 1',4-dihydroxytriazolam. 2. Major metabolites found in the urine were 1',4-dihydroxytriazolam, 1'-hydroxy-DCTB and DCTB in rats; 1'-hydroxytriazolam, 4-hydroxytriazolam and conjugated 1'-hydroxytriazolam in dogs. 3. Major metabolites found in the faeces were 4-hydroxytriazolam in rats; 1'-hydroxytriazolam and 4-hydroxytriazolam in dogs. 4. Conjugated 4-hydroxytriazolam was the major metabolite in both the original and reabsorbed bile of rats. 5. Major metabolites in free form in the plasma were 4-hydroxytriazolam and 1'-hydroxytriazolam in rats; triazolam and 1'-hydroxytriazolam in dogs. 6. The major metabolite in the brain was triazolam, but those in the liver were 4-hydroxytriazolam and triazolam, and in the kidneys were 4-hydroxytriazolam and 1',4-dihydroxytriazolam. 7. Major metabolites in the urine, faeces, plasma and brain after 7-, 14- or 21-day repeated dosing in rats were not much different in type and ratio from those after single dosing. 8. Unchanged triazolam and 1'-hydroxytriazolam were the major metabolites in the plasma, placenta, foetus and amniotic fluid in pregnant rats. 9. There was no change in hepatic aniline hydroxylase and aminopyrine-N-demethylase activity from controls in rats given oral dose of [14C]triazolam for 14 days.

Animals↗
PubMed1979

Potentiation of ethyl para-nitrophenyl phenyl-phosphonothioate (EPN)-induced inhibition of liver microsomal carboxylesterase by NAD in vitro in rats.

The higher inhibition of liver microsomal carboxylesterase (CEase) by EPN, as compared to that of acetylcholinesterase (AchE) may be, at least in part, explained by the present findings that NAD potentiated the anti-CEase, but not anti-AchE, action of EPN. This phenomenon was referred to as "NAD-effect" in this paper. NAD-effect was not due to the increased formation of oxygen analog of EPN (EPN=O) by NAD addition through liver microsomal cytochrome P-450 catalyzed monoxygenase, because the amounts of EPN=O formed during incubation in the presence and absence of NAD were not significantly changed as shown by gaschromatography-mass spectrometric estimations. In addition, HAD-effect could be observed in the experiments even under carbon monoxide atmosphere. Such NAD-effect was observed only when NAD, EPN and an unidentified component bound to liver microsomal membrane were co-existent in the incubation mixture.

Anaerobiosis↗
PubMed1979

Differences of affinity and energetics of the active transport systems for amino acids in Chang liver cells.

The plasma membrane of Chang liver cells was shown to have at least two distinct active transport systems, one with preferential affinity for glycine and one for leucine. The uptakes of glycine and leucine were specificially inhibited by Me-AIB and b-BCH, respectively. The uptake of glycine decreased remarkably within 10 min on incubation with DNP (2 mM), KCN (5 mM), and malonate (20 mM) under aerobic conditions, along with a decrease of cellular ATP concentration to as low as 1/4 of normal, while the uptake of leucine was not depressed under these conditions. Leucine uptake was, however, greatly reduced within 10 min on incubation with DNP plus ICH2CONH2 (5 mM), when the cellular ATP was estimated at about 0.066 mM. The active transport of leucine, but not that of glycine, was accompanied by further acidification of the intracellular fluid, which was lower in pH than the extracellular fluid by approximately 0.3 unit without addition of amino acid to the medium.

Adenosine Triphosphate↗
PubMed1979

Effects of water-immersion stress on gastric secretion and mucosal blood flow in rats.

The correlation between acid secretion and mucosal blood flow in the rat stomach during stress loading was determined to provide clues to the etiology of the gastric ulceration which thus occurs. The gastric acid output was increased remarkably by water-immersion stress at 23 degrees C, and this increase lasted while the stress was given, yet the mucosal blood flow did not show a corresponding increase. In rats stressed for 3 hr, ulcerative changes were observed in the glandular portion of the stomach. The stress-induced increase in acid output correlated well with the severity of erosions. Pretreatment of animals with atropine 10 microgram/kg, given subcutaneously, or vagotomy, inhibited the increase in acid output and also inhibited the ulcer formation caused by the stress: however, the mucosal blood flow in these animals decreased significantly. These results suggest that when there is an elevation of gastric acid secretion with no parallel increase in mucosal blood flow, gastric ulceration may occur under conditions of stress.

Animals↗
PubMed1979

Induction of NADH-dependent aldehyde reductase by successive administration of barbiturates in rat brain.

The effect of long-term administration of phenobarbital (PB) or barbital for five weeks on brain aldehyde reductase (A1R) and aldehyde dehydrogenase (A1DH) activities in the rat was studied. Mitochondrial (m)-A1DH and NADH-dependent A1R activities were significantly increased over control values after five-week treatment with PB or barbital, while no significant alteration of supernatant (s)-A1DH and NADPH-dependent A1R activities was observed under the same condition. Increase in m-A1DH activity by the treatment with barbiturates was recovered to the control level, however, increased activity of NADH-dependent A1R was maintained even after the cessation of the treatment. In groups of rats pretreated with barbiturates for five weeks, no animals were induced to sleep after intracerebroventricular injection of PB, and this finding strongly suggests the decrease in sensitivity of rats to barbiturates.

Aldehyde Oxidoreductases↗
PubMed1979

Changes in serotonin turnover and the brain sensitivity to barbiturates by disulfiram treatment in rats.

The influence of intraperitoneal administration of disulfiram on the serotonin (5HT) turnover and the brain sensitivity to barbiturates were investigated in rats. Treatment of the animals with 200 mg/kg disulfiram resulted in the prolongation of duration of barbiturate-induced hypnosis. This indication and increment of the brain sensitivity to barbiturates after disulfiram treatment. Under the identical condition, disulfiram caused both the reduction of turnover of 5HT and the elevation of 5HT levels, although this effect was less potent than that of phenobarbital. Furthermore, simultaneous administration of disulfiram and phenobarbital resulted in the severe retardation of 5HT metabolism. These results strongly suggest that disulfiram potentiates the hypnotic action of barbiturates by altering 5HT metabolism in rat brain.

Animals↗
PubMed1979

Effects of barbital and disulfiram on the metabolism of intracerebroventricularly administered [14C]-5-hydroxytryptamine in rats.

Effects of barbital and disulfiram on the metabolism of serotonin (5-HT) in vivo were studied. One hr after intracerebroventricular injection of [14C]-5-HT (3 nmoles, 0.5 muCi), the levels of the total and deaminated radioactive materials were increased in rats receiving either barbital or disulfiram, as compared to those of control rats. In addition, an additive effect was observed by a combined administration of these two drugs. The results in this paper strongly suggest that barbital and disulfiram inhibit the metabolism of 5-hydroxyindoleacetaldehyde (5-HIAAld), a first deaminated metabolite in 5-HT metabolism.

Animals↗