The intestinal absorption of dl-α-tocopherol (VE) from various micellar solutions was studied by the in situ recirculating perfusion in rat small intestine. The perfused micellar solutions of VE were formed by sodium taurocholate (STC), sodium taurodeoxycholate (STDC) or polysorbate 80 (PS-80). The absorption ratio of VE was STC>STDC>PS-80 micellar solutions. The addition of egg lecithin (PC) to all micellar solutions caused the decrease of the absorption. The absorption ratio did not necessarily have a simple correlation with the VE solubilization in these micellar solutions. And it was also found that the absorption ratio correlated with the micellar size and with net water flux in the intestinal lumen.

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Chemical composition and physicochemical properties of an immunomodulator, which is a non-dialyzable and acetone precipitable material(s) extracted with hot water from Angelica actiloba KITAGAWA (Yamato Tohki) (AIP), were investigated. AIP was composed of about 90% sugar and 10% protein. The major polysaccharide was identified as pectic substance(s) because its main component sugars were found to be arabinose, glucose, and galacturonic acid by gas liquid chromatographic analysis. The pectic substance(s) was not concerned with the mitogenicity of AIP since the activity was similar before and after pectinase(endo-polygalacturonase) treatment. More than half of the mitogenicity was destroyed by acid or alkali treatment. With pronase treatment, the activity was not affected, but the molecular weight of the mitogen was lowered. In addition, the mitogenic substance was partially purified from AIP by pectinase treatment and Westphal's phenol/water fractionation. The partially purified mitogenic substance(s) was rich in protein. These facts suggest that the mitogenicity of AIP was carried by a heat stable and protease resistant protein.

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The effect of ethanol on maternal and neonatal hepatic heme and drug metabolizing systems was determined. Ethanol (16%, w/v) was administered orally as drinking solution to pregnant or lactating rats at different pre-and post-natal stages. The dams and pups were sacrificed on days 7, 14 and 21 after parturition, respectively. Ethanol administration to lactating rats from just after birth caused an appreciable decrease in the maternal and neonatal body and liver weights. In addition, the activities of nicotinamide adenine dinucleotide phosphate-cytochrome c reductase, nicotinamide adenine dinucleotide-cytochrome b₅ reductase and heme oxygenase were significantly enhanced in the livers of neonates whose mothers were exposed to the ethanol during only first week of lactation, but those activities were not altered in the maternal livers. However, no remarkable alterations were observed in the contents of cytochrome P-450 and b₅ and the activities of aminopyrine demethylase, aniline hydroxylase and δ-aminolevulinic acid synthetase in the livers of neonates from mothers who had received ethanol during lactation period or last week of gestation, although the activities of aminopyrine demethylase and aniline hydroxylase were enhanced significantly in lactating dams by ethanol consumption for 14d after parturition.

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5-O-Substituted derivatives of 5-hydroxypicolinic acids were synthesized from nojirimycin and studied for their antihypertensive activity in unanesthetized spontaneously hypertensive rats (SHRs) restrained in wire mesh cage and acute toxicity in mice. 5-n-Butoxy-picolinic acid (ND-186) was found to have antihypertensive activity comparable to fusaric acid and lesser acute toxicity. Introduction of halogeno group, in particular trifluoromethyl group to the ω-position of 5-n-butoxy group resulted in the enhancement of antihypertensive activity. The acute toxicity was also lowered 3-5 times compared to that of fusaric acid. Replacement of alkyl group with phenyl group resulted in a slight increment of activity. Some of ester derivatives of ND-186 potentiated the antihypertensive activity and reduced the acute toxicity. There was good correlation between partition coefficient (log P) of ester groups and their antihypertensive activities ; compound with higher lipophilicity showed higher antihypertensive activity under the condition of oral administration. However, esterification of other compounds such as 5-halogenoalkoxy-and 5-(substituted) phenoxypicolinic acid was not accompanied with activity increment. Considering from the balance of the antihypertensive activity in SHRs and the acute toxicity in mice, 5-(5', 5', 5'-trifluoropentoxy)-picolinic acid was selected as a candidate for further evaluation.

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Perry's hypothesis that hydrazine (Hz) derived from isoniazid (INH) treatment plays an important role in the elevation of brain γ-aminobutyric acid (GABA) levels¹⁾ was reexamined by measuring Hz and GABA levels in the brain after the treatment with 50 mg/kg of INH or different doses of Hz. The treatment with 50 mg/kg of INH to rats resulted in the elevation of GABA levels in rat whole brain. The maximum levels of GABA increased about twice at 4h from 2.06±0.4μmol/g wet wt. in the control group to 3.61±0.4μmol/g wet wt. in INH treated group. In this case, brain levels of Hz ranged from 25.6 to 80.8 ng/g wet wt. within 10 h. On the other hand, Hz levels after the treatment with 0.5 mg/kg of Hz were about five times higher than those after INH treatment. However, 0.5mg/kg of Hz treatment did not increase brain GABA levels at all. Perry's hypothesis was denied by the fact that brain Hz levels after INH treatment were too low to elevate brain GABA levels.

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Methanol extracts of bracken frond and rhizomes prepared using a metallic extraction vessel, were proved incapable of producing bracken poisoning in calves. Nevertheless, they contained appreciable quantities of pterosins and pterosides. Thus the poisonous principle(s) in bracken responsible for the toxicological effects are not associated with these major sesquiterpenoids of the plant.

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Total glutathione (GSH and GSSG) level, and the activities of γ-glutamylcysteine synthetase, γ-glutamyltranspeptidase (γ-GTP), glutathione S-transferase (GST), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) in the liver were investigated in rats, mice, guinea pigs and hamsters. Hepatic GSH level in rats, mice, guinea pigs and hamsters were 7.1, 7.8, 3.5 and 5.4mM, respectively. The lower level of GSH in guinea pigs seems to be in part attributed to the higher activity of hepatic γ-GTP, an enzyme which catalyzes GSH breakdown. Moreover, a marked species difference in the activities of GST, GSH-Px and GR was also observed. A 48 h-fasting resulted in a decrease of GSH and GSSG levels in rats, mice and guinea pigs, but not in hamsters. In addition, both nicotineamide adenine dinucleotide phosphate-and ascorbate-dependent lipid peroxidation produced by 9000×g supernatant fraction in fasted animal species occurred most highly in the rat followed by hamster and guinea pig, and almost undetectable in mice. Thus, it suggests that the occurrence of lipid peroxidation in fasted animals may not be related to the hepatic GSH level, and rather, a lack of occurrence of lipid peroxidation in fasted mice may be due to the increased activity of GSH-Px activity.

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This study was undertaken to examine a possible role of bis(methylmercuric) selenide(BMS) in selenite-induced redistribution of methylmercury in rats. Pretreatment of diethylmaleate(DEM), which depletes tissue reduced glutathione(GSH), completely suppressed the significant increase of BMS produced by selenite injection in the blood of methylmercury-treated rats. Its inhibitory effect was also observed in the kidney and brain. Under the same conditions, the characteristic accumulation in the brain and testis of total mercury induced by selenite was markedly inhibited by DEM pretreatment. Total mercury in these tissues was not altered by DEM alone and BMS in the blood existed in the erythrocytes, but not in the plasma. Thus, it seems likely that the suppressed formation of BMS in the erythrocytes mainly leads to the decreased accumulation of total mercury in the brain and testis.

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Inductive effects of pretreatments with a phenobarbital(PB)-type 2, 4, 5, 2', 4', 5', -hexachlorobiphenyl(HCB), a 3-methylcholanthrene(MC)-type 3, 4, 5, 3', 4', -pentachlorobiphenyl(PenCB) and a mixed type polychlorinated biphenyl (PCB) mixture, Kanechlor(KC-)400 as well as PB and MC on the hepatic and pulmonary microsomal mixed function oxidases(MFOs) were examined and compared using male Wistar rats. Hepatic cytochrome P-450(448) content was increased 2-to 4-fold by pretteatment with all inducers tested, whereas the pulmonary content was slightly elevated only by the MC-type (MC and PenCB) and mixed type inducers. Benzphetamine(BZ) N-demethylase activity in the liver was strongly enhanced by the PB-type (PB and HCB) and mixed type inducers, but not affected by MC and suppressed by PenCB. Pulmonary BZN-demethylation was not affected by pretreatments with the MC-type and mixed type inducers while both PB-type inducers decreased the activity.The PB-type inducers, showing a weak inducibility for aryl hydrocarbon hydroxylase (AHH) in the liver, also diminished the activity in the lung. In contrast, a marked enhancement of AHH activity in both organs was caused by pretreatment with the MC-type and mixed type inducers. AHH activity in both organs from PenCB-treated rats was highly sensitive to α-naphthoflavone but almost insensitive to SKF 525-A. These results strongly suggest that the pulmonary MFO in rats in inducible only with MC-type but not with PB-type PCB unlike the hepatic MFO.

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Experimental allergic encephalomyelitis (EAE) is one of the experimental models of human demyelinating diseases and recently is regarded also as useful model for studying cell-mediated autoimmune diseases. Because of the possibility of induction of systemic changes in this model, we investigated enzymatic changes in serum and main organs of the diseased animals, including brain, spinal cord, limb muscle, heart muscle, spleen, liver and kidney. The enzymes measured consisted of 7 aminopeptidases, 5 endopeptidases, 3 glycosidases, creating kinase, phosphatase and esterase. Significant changes of many enzymatic activities occurred in all the organs tested in 1 to 2 weeks after the administration of EAE antigen, myelin basic protein (MBP). Interesting correlations of the pattern of enzymatic changes were seen among most of the organs tested. Those patterns changed in the course of the 2 weeks and there remanied marked changes characteristic for each organ. This model may represent some type of systemic autoimmune diseases.

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Although our previous studies demonstrated marked changes in the activities of hydrolytic enzymes in guinea pigs afflicted with experimental allergic encephalomyelitis (EAE), it is possible that at least some parts of them were due to the effects of Freund's complete adjuvant (FCA) per se used for immunization. Thus we tried to find the property of the enzymatic changes in the tissues of limb muscle, heart muscle, spleen, liver, kidney, brain, spinal cord and serum induced by the administration of FCA alone to the guinea pigs. FCA caused rather intensive enzymatic changes in evey organ tested. When the patterns of these enzymatic changes were compared with those of the animals afflicted with EAE, a significant correlation was seen only in forelimb muscle at 1 week after the injection of the agents, whereas at 2 weeks significant correlations were seen in heart and liver. Although these results indicate that in some organs there are some similarities between the two experimental conditions, the degree of determination for this phenomenon was not high, being 28% at the highest. This means that most of the enzymatic changes seen in the animals afflicted with EAE could not be explained by the effects of FCA. It was concluded that FCA causes unique and systemic enzymatic changes when administered to the animals.

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Anti-inflammatory assays on the carrageenin-induced edema and scald-induced hyperalgesia in the hindpaw of rats were studied on polysaccharides obtained from the fruit bodies of various fungi (polysaccharide AC, BC : Tremella fuciformis ; MEA, MHA, MCW-A, MCW-N : Auricularia auricula-judae ; T-2-HN : Dictyophora indusiata ; G-A : Ganoderma japonicum). The purified polysaccharides MHA, MCW-A, G-A and T-2-HN exhibited a significant inhibitory effect on carrageenin edema. Among these polysaccharides, T-2-HN (partially O-acetylated α-D-mannan) also showed the marked inhibitory effect on scald hyperalgesia. We have found that T-2-HN has more potent anti-inflammatory activity than phenylbutazone in the above two inflammatory models. Since the purified polysaccharide is free from protein and lipid, it is clear that anti-inflammatory effect arises from the polysaccharide itself. The polysaccharides (T-2-HN, locust bean gun, xanthan gum) had little effect on the metabolism of arachidonic acid in canine platelets. The mechanism of the anti-inflammatory activity of the polysaccharide remains obscure.

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The salivary excretion of warfarin was investigated following intravenous and oral administration to rabbits. The salivary decay curves following intravenous injection (50 mg/kg) fitted to the two -compartment open model. On the other hand, following oral administration (100 mg/kg) the disposition of warfarin fitted to the one-compartment open model. There was a good linear relationship between the warfarin concentrations in saliva and plasma. The saliva vs. plasma (S/P) ratio was approximatelly 0.07. A good correlation was also observed between the warfarin concentrations in saliva and plasma protein-unbound fraction. The saliva vs. plasma protein-unbound fraction (S/P_f) ratio was approximatelly 0.92. Therefore, salivary concentration of warfarin corresponded with plasma free warfarin concentration. Furthermore, warfarin concentration in saliva was correlated with pharmacological effect, prothrombin complex activity. These results suggested that salivary warfarin concentration which was correlated with pharmacological effect had a possibility of utilization in pharmacokinetic studies and therapeutic drug monitoring.

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In view of the reduction of side effects as well as the enhancement of anti-tumor activities of anticancer drugs, we have been interested in the combined use of Chinese medicines with them. In the present study we attempted to examine the effects of Chinese prescription, Juzentaihoto (JTX), combined with mitomycin C (MMC). JTX is consisted of Astragali radix, Chinnamomi cortex, Rehmanniae radix, Paeonia radix, Cnidii rhizoma, Atractylodis lanceae rhizoma, Angelicae radix, Ginseng radix, Hoelen and Glycyrrhizae radix. In BDF₁-mice which were implanted with P-338 leukemic cells, JTX prolonged significantly the average survival days of MMC-treated group. In tumor-free BDF₁-mice, JTX improved the leukopenia and the body weight loss which were caused by MMC. Additionally, JTX delayed the appearance of deaths by lethal dosis of MMC. These results indicate that JTX enhances the anti-tumor activity of MMC and lessens the adverse effects of it. JTX may be useful for patients undertaking MMC treatment.

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The effect of environmental temperature on the content of cytochrome p-450 or the activity of nicotinamide adenine dinucleotide phosphate-cytochrome c (NADPH-cytochrome c) reductase was examined by using microsomes prepared form rats kept at 30°C or 15°C for 14 d. The warm exposure (30°C for 14 d) resulted in a significant reduction of the activity of NADPH-cytochrome c reductase though the content of cytochrome P-450 was not changed. The level of thyroxine and 3, 3', 5-truodothyronine was reduced by the warm exposure. From the present observation, it was suggested that the effect of environmental temperature on the metabolism of drgus was due to the activity of NADPH-cytochrome c reductase mediated by the level of thyroid hormone.

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