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Biomedical subjects

T Oida

Publications and source records attributed to T Oida.

27 records · Page 2Linked to original sources
PubMed1990

DNA-glutathione adducts derived from vic-dihaloalkanes: mechanisms of mutagenesis.

The conjugation of the prototype dihaloalkane ethylene dibromide (EDB) with glutathione (GSH) yields S-(2-bromoethyl)GSH, which gives rise to S-[2-(N7-guanyl)ethyl]GSH as the major DNA adduct (greater than or equal to 95%). All reaction steps have SN2 character. Another minor DNA and RNA adduct is S-[2-(N1-adenyl)ethyl]GSH, formed in vitro and in vivo. These adducts have similar half-lives in vivo. Enhancement of GSH conjugation or inhibition of cytochrome P-450 IIE1 oxidation enhances DNA adduct levels in vivo and GSH depletion lowers levels. The mercapturic acid N-acetyl-S-[2-(N7-guanyl)ethyl]cysteine is excreted in urine and may find use as a biomarker. A series of compounds of the general structure RSCH2CH2Cl has been used to alkylate Salmonella typhimurium TA100. The ratio of (guanyl) base-pair mutations to N7-guanyl adducts varies dramatically, with S-(2-chloroethyl)GSH apparently producing the most potent guanyl adduct. This mutagenicity is not due to SOS response or alkylation specificity. Physical studies with modified oligonucleotides indicate that the N7-guanyl substitution weakens G-C pairing but does not in itself alter the selectivity of pairing to C in an isolated oligomer.

Alkylation↗
PubMed1989

Use of antisera in the isolation of human specific conjugates of haloperidol.

1. Three conjugated metabolites of haloperidol were isolated from urine of patients on haloperidol and purified by h.p.l.c. with immunological detection, using three types of anti-haloperidol antisera. 2. Structures of the metabolites were: a sulphate conjugate of the 2-hydroxylated 4-fluorophenyl ring of reduced haloperidol (MH-1), a glucuronide conjugate at the same position as MH-1 (MH-2), and a glucuronide conjugate of the hydroxy group of haloperidol (MH-3). 3. MH-3 was the main urinary metabolite in volunteers receiving haloperidol, who excreted 18% of the dose in the 24 h urine as MH-3, while other conjugates were less than 1%. MH-3 could not be hydrolysed with beta-glucuronidase, due to steric hindrance. 4. Immunological detection of conjugated metabolites is very useful in metabolic studies in humans because of its sensitivity and specificity.

Adult↗
PubMed1986

Proton nuclear magnetic resonance study on the multimode interactions of human serum albumin with drug molecules.

The interactions of human serum albumin (HSA) with a number of ligands (mostly drugs) were examined by proton nuclear magnetic resonance spectroscopy. Ligand presence-absence difference spectra of HSA solutions were measured. Nonspecifically bound drugs such as tiaramide showed difference spectrum patterns which were similar to the spectra of the drugs themselves but were broadened as to the line-widths of signals. Thus, the difference spectra of these drugs reflect only the changes in the surroundings of the drug molecules, that is, between the bound and free states. In contrast, specifically bound drugs like ibuprofen and warfarin showed difference spectra in which signals from the HSA molecule only were observed. Furthermore, according to the characteristic peaks in these difference spectrum patterns, specifically bound drugs may be classified into several groups; the drugs in the first group bind to the ibuprofen binding site, those in the second group to the warfarin binding site, and those in the third group to sites other than the warfarin and ibuprofen sites. These findings suggest that the specific binding of drugs to HSA brings about a conformational change of this protein which is specifically correlated to the binding site.

Binding Sites↗
PubMed1986

1H-NMR study on the interactions of human serum albumin with free fatty acid.

Binding of free fatty acid (FFA) to human serum albumin (HSA) was studied by 1H-NMR spectroscopy. Addition of FFA to defatted HSA at a mole ratio (FFA/HSA) up to 4 caused a small change in the NMR spectrum of HSA. The integrated intensity of sharp signals of the histidine C2 proton region of HSA decreased as the mole ratio was increased from 0 to 4 for both medium chain (lauric acid) and long chain (palmitic acid, stearic acid, and oleic acid) FFA's. By contrast, when the mole ratio was increased above 4, several histidine C2 proton signals coalesced and sharpened. Therefore, the HSA molecule appears to have a different conformation on binding with more than 4 FFA molecules, which allows increased local motions of HSA. By analyzing the NMR difference spectra of HSA with various amounts of FFA, the conformational change of HSA was investigated in more detail. The difference spectrum between [HSA + 2FFA] and [HSA + FFA] was almost the same as the difference spectrum between [HSA + FFA] and [HSA], which suggests that one primary site binds a pair of FFA molecules. These results are consistent with those of a spectroscopic study with polyene fatty acids (Berde, C.B., et al. (1979) J. Biol. Chem. 254, 391-400). The existence of a bimolecular complex of FFA molecules in aqueous solution may facilitate this type of binding. Similarly, it was found that the third and fourth FFA molecules were bound to a secondary site on HSA, because the difference spectrum between [HSA + 4FFA] and [HSA + 3FFA] was nearly equal to the difference spectrum between [HSA + 3FFA] and [HSA + 2FFA]. Further addition of FFA resulted in a drastic spectral change of HSA. The NMR difference spectrum between HSA solutions with perdeuterated FFA and those with undeuterated FFA gave the 1H-NMR spectra of FFA molecules bound to HSA. Titration of FFA revealed that, in the binding to the primary site of HSA, the carboxyl group of FFA is tightly bound to the protein, whereas the methyl group is not so firmly bound. In contrast, in the binding to low affinity sites, the methyl group is bound to HSA as tightly as other portions of the molecule.

Binding Sites↗
PubMed1985

The metabolism of gliclazide in man.

Gliclazide, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(4-methylphenylsulphonyl)urea, was orally administered to five healthy male volunteers at a dose of 40 mg. Urine contained seven metabolites classified into two types according to the site of biotransformation. Two major metabolites, 1-(3-azabicyclo[3,3,0]oct-3-yl)-3-(4-carboxyphenylsulphonyl)urea and 1-(3-azabiyclo[3,3,0]oct-3-yl)-3-(4-hydroxymethyl-phenylsulphon yl)urea, of the first type were oxidized at the methyl group of the tolyl group. Five metabolites of the second type including two glucuronides were hydroxylated at a specific site in the azabicyclo-octyl ring (b beta, 7 beta and 7 alpha). The molecular conformation of this type of metabolites could explain the existence of conjugates of the beta-hydroxy groups in the azabicyclo-octyl ring and the absence of those of the alpha-hydroxy group. Only the unchanged drug was detected in plasma. The peak concentration at four hours after dosing was 2.6 +/- 0.2 microgram/ml, and the elimination half-life in plasma was 8.1 +/- 1.1 hours which was apparently determined by the rate of metabolism. Identified metabolites excreted in urine accounted for 45% of the dose in 24h and 61% in 96h, indicating that this was the major excretory route.

Adult↗
PubMed1979

An experimental study on histamine H2-receptor antagonist on calcium, gastrin and histamine induced gastric acid secretion in rat.

The suppressive effect of histamine H2-receptor antagonist, cimetidine, on gastric secretion was investigated in Ghosh-Schild rat. The study above was done in basal state under infusing normal saline (1 ml/h) and stimulated state by histamine-di-chloride (3.5 mg/kg-h), tetragastrin (50 mcg/kg-h) or calcium chloride (4 mg/kg-h). Dose related increase of cimetidine (1.7, 3.5, 7.0 and 14.0 mg/kg-h) were observed and correlated with the degree of inhibition of acid secretion. Cimetidine had a potent inhibitory activity on either basal and stimulated acid output by the agents above. Basal acid secretion was completely abolished by 3.5 mg/kg-h of cimetidine to the level of anacidity. The degree of inhibition by the same dose of cimetidine was different among the agents used as stimulant on acid secretion and it followed in the order of calcium, gastrin and histamine subsequently. This study indicated that histamine H2-receptor participated the gastric secretion induced by either gastrin or calcium other than histamine itself. This fact indicated the important role of endogenous histamine in gastric secretion induced by calcium and gastrin.

Animals↗