The N-hydroxyl and/or N-acetoxy derivatives of carcinogenic 4-aminoazo dyes, which were thought to be proximate and ultimate metabolites, were synthesized in our laboratory in 1975, and their chemical and biological characteristics were further examined. The results strongly supported the hypothesis that the metabolic conversions, N-hydroxylation and its O-acylation, of carcinogenic aromatic amines are important processes for their carcinogenicity. Carcinogenic aromatic amines such as heterocyclic aromatic amines and aminoazo dyes induced predominantly cytochrome P450IA2 (CYP1A2), which is responsible for the mutagenic activation and N-hydroxylation of the amines in the rodent. The induction rate and total activity of this enzyme were well correlated with sex, species, and target organ differences in hepatocarcinogenic susceptibility of animals to the aromatic amines. During hepatocarcinogenic process with an aromatic amine, the expression and induction of CYP1A2 decreased especially in preneoplastic liver cells as judged by the expression of a placental form of glutathione S-transferase.
Progress in molecular biological studies on the H+/K+-ATPase (gastric proton pump) now enables us to discuss not only its subunit protein structures and catalysis but also the organizations of its subunit genes and their cell-specific transcription. The primary structures of the catalytic α and glycosylated β subunits and their transmembrane topology are similar to those of the corresponding subunits of Na+/K+-ATPase. The exon/intron organizations of the genes for the H+/K+-ATPase α and β subunits are closely similar to those of the corresponding subunits of Na+/K+-ATPase, suggesting that the α and β subunit genes of the two ATPases were respectively derived from common ancestors. In contrast to ubiquitous Na+/K+-ATPase, the H+/K+-ATPase is expressed specifically in gastric parietal cells. Consistent with this fact, we found novel zinc finger proteins which are present in the gastric parietal cells and recognize a gastric sequence motif in the 5'-upstream regions of the H+/K+-ATPase α and β subunit genes. The proteins are likely to play important roles in the transcriptional regulation of the parietal cell specific genes.
This review describes the modes of mice radiation injuries induced by soft X-irradiation under various conditions and the protective effects of several kinds of substances on these injuries. The models of radiation injuries in this study were bone marrow death after lethal irradiation, skin damage induced by irradiation with long length soft X-ray and leukocytopenia in the peripheral blood after sublethal irradiation. Two bioassay methods were established for the survival effect on the lethal irradiation and protective potency on the skin damage induced by soft Xirradiation. The protective potencies of various sulfur compounds, related compounds of ferulic acid, nucleic acid constitutional compounds, crude drugs and chinese traditional medicines were determined and then many effective drugs were recognized. Effective components in the methanol extracts of Cnidii Rhizoma and Aloe arborescens recognized as radioprotectable were fractionated. As a result of these studies, it was observed that the active principles in Cnidii Rhizoma were identified as ferulic acid and adenosine. The scavenge action of active oxygens, a protective effect on the damages of deoxyribonucleic acid and superoxide dismutase by in vitro soft X-irradiation were evaluated as radiation protective mechanisms.
The majority of medicines developed for narcotic and stimulant dependence were agonists or antagonists of neurotransmitters and their receptors. Recently it has been shown that the nervous system, the endocrine system and the immune system are regulated by mutual interaction. The nervous system and the endocrine system are influenced by an immunomodulator, and the immune system is regulated by a neurotransmitter. In this report, medicines for morphine and cocaine dependence are first surveyed and then medicines for drug dependence through the activation of the immune system are introduced including our results which show the effect of macrophage activator such as LPS on morphine and cocaine dependence. The LPS purified from Pantoea agglomerans showed a relief effect on physical dependence of morphine and psychic dependence of cocaine, while it induced endogenous opioid, β-endorphin. The induction of β-endorphin was recognized to be in synchrony with the time course and dose response of the relief of dependence. These data suggest the participation of endogenous opioid such as β-endorphin induced by LPS after the activation of macrophage leading to the relief of morphine and cocaine dependence.
F-0401 is a newly synthesized dihydropyridine derivative with both antagonistic activity on platelet-activating factor (PAF) and inhibitory action on thromboxane A2 (TXA2) synthetase activity. In the present study, we examined the effects of F-0401 on platelet aggregations in vitro and ex vivo in rabbits. F-0401 prevented PAF-, arachidonic acid (AA)- and collagen-induced platelet aggregations in vitro, but did not prevent the aggregation by ADP. The inhibitory effect of F-0401 on the aggregation by PAF (IC50 value : 4.3×10-6M) had the same potency as that of CV-3988 (a PAF antagonist) and ozagrel a (TXA2 synthetase inhibitor). Ex vivo studies also revealed that the anti-aggregatory effect occurred 1 h after the treatment of F-0401 (>10 mg/kg, p.o.) and this effect had a tendency to last for 6 h. Nicardipine prevented the platelet aggregation only by PAF (IC50 value : 6.6×10-5M) in vitro. However, the preventive effect was not seen ex vivo. On the other hand, neither nifedipine nor flunarizine showed any effect on the stimulant-induced platelet aggregation in rabbits. These results suggest that F-0401 has anti-aggregatory action, which is attributable to both PAF antagonistic action and TXA2 synthetase inhibition in vitro and ex vivo.
The determination of the constituents of crude drugs in drinkable preparations by high performance liquid chromatography was established. As a result of the examination about the crude drugs which were blended in 16 kinds of commercial drinkable preparations, Epimedii Herba, Ginseng Radix and Royal jelly had more blending frequency or contents. So the determination of icariin, ginsenoside Rg1 and 10-hydroxy-2-decenoic acid which were characteristic constituents of each crude drug was established. The determination of hypoxanthine which was isolated from Cervi Parvum Cornu and had monoamine oxidase inhibitory activity, and choline which was found in Cistanchis Herba and Epimedii Herba much more than other crude durgs in 16 kinds of drinkable preparations was also established. The contents of each constituent in several kinds of drinkable preparations were determined by these established methods.
The interaction between sodium hyaluronate (HA) and 6 kinds of tetracycline (TCs) was investigated by dissolution tests, conductivity, viscosity and turbidity measurements. The 6 TCs were tetracycline (TEC), oxytetracycline (OTC), doxycycline (DOC), methacycline (METC), minocycline (MINC) and chlortetracycline (CTC). In dissolution tests, the release of TCs from the HA solution contained in the cellulose tube was measured and it was found that the 50% release time (T50) of TCs was prolonged with the increase of HA concentration. And the dependence of T50 on HA concentration was different in TCs : the release of METC was most delayed and that of OTC was least affected. By measuring the conductivity of TCs solutions, the binding of TCs to HA was suggested. In viscosity measurements of the HA solution at various pHs, the increase of viscosity was observed by the addition of METC. However in the case of OTC such an increase was not observed. The dissolution tests at various pHs were further tried and the release rate of METC depended on the pH, while that of OTC showed no dependency. Finaly, it was found that T50 of TCs from the HA solution correlates well with the literature values of apparent partition coefficients of TCs between n-octanol and aqueous buffers. Comparing T50 of 6 TCs from carboxymethylchitin (DS=0.56) solution, it was clarified that the lipophilicity of TCs are more effective to retard the release in the case of the HA solution. From the above results, an electrostatic interaction between HA and TCs can be assumed to be almost similar among 6 TCs. Therefore it was presumed that the difference of release profiles in the dissolution tests were due to the hydrophobic interaction between HA and TCs.