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T Inaba

Publications and source records attributed to T Inaba.

At least 487 records · Page 27Linked to original sources
PubMedDate not supplied

Glutamine-enriched enteral diet enhances bacterial clearance in protected bacterial peritonitis, regardless of glutamine form.

BACKGROUND: The effects of glutamine (Gln)-enriched enteral diets on bacterial clearance were investigated in a rat protracted peritonitis model. The effects of the Gln form, peptide-based vs free amino acid-based, were also compared. METHODS: Twenty-three rats underwent gastrostomy. An osmotic pump was implanted in the peritoneal cavity. The rats received a continuous intragastric infusion of one of three diets: Gln-depleted (Gln 0), Gln-enriched with the Gln in free amino acid form (Gln F), or Gln-enriched with the Gln in oligopeptide form (Gln P). The three formulas were isocaloric and isonitrogenous. The pumps delivered a continuous infusion of Escherichia coli, starting at 48 hours after implantation, for 24 hours. Then, the animals were killed. RESULTS: Bacterial numbers in peritoneal lavaged fluid (PLF) and the liver were significantly lower in the Gln P and Gln F groups than in the Gln 0 group. The bacterial number in PLF correlated with that in the liver. Neither the number nor the population of peritoneal exudative cells differed among groups. Plasma levels of proline, alanine and citrulline were significantly higher in the Gln P and Gln F groups than in the Gln 0 group. Both Gln supplemented groups showed significantly greater villous height, crypt depth, and numbers of mitoses per crypt in the small intestine than the Gln 0 group. CONCLUSIONS: Supplemental Gln enhances peritoneal and hepatic bacterial clearance, regardless of Gln form. Gln-enriched may be more beneficial than Gln-depleted enteral diets in peritonitis.

Animals↗
PubMedDate not supplied

T-cell associated antigen-positive B-cell lymphoma.

We immunophenotyped 128 patients with B-cell non-Hodgkin's lymphoma (B-NHL) of various histological subtypes using two-color flow cytometry (FCM), and found that lymphoma cells obtained from 31 patients (24.2%) coexpressed at least one of the following T-cell associated antigens (T-Ag); CD2 (2.3%), CD5 (18.0%) or CD7 (6.3%). Moreover, 3 patients expressed two kinds of T-Ag (CD2/CD5, CD2/CD7 or CD5/CD7) as reported by other investigators. Though we could not find coexpression of CD3, CD4 or CD8 antigen in any patients analyzed in our study, such T-Ag(+) B-NHL have also been reported in the literature. As clinical features, extranodular involvement and higher International Prognostic Index (high and high intermediate) seemed more frequent in T-Ag(+) B-NHL than T-Ag(-) B-NHL in our study. Such prognostic significance of T-Ag expression is also reported by other investigators especially in CD5(+) diffuse large B-cell lymphoma. In addition, two-color FCM for detecting such aberrant T-Ag expression in B-NHL is useful for monitoring the minimal residual disease in the subgroup with T-Ag(+) B-NHL.

Antigens, CD7↗
PubMedDate not supplied

Roles of thymidylate synthase and dihydropyrimidine dehydrogenase in tumor progression and sensitivity to 5-fluorouracil in human gastric cancer.

BACKGROUND: The role of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) enzyme activities in tumor progression and sensitivity to 5-fluorouracil (5-FU) were evaluated. MATERIALS AND METHODS: TS and DPD activities were measured in 81 clinical samples of gastric cancer. TS and DPD activities were determined by 5-fluorodeoxyuridine monophosphate binding assay and by radioenzymatic assay, respectively. Sensitivity to 5-FU was determined by in vitro ATP assay. RESULTS: There was no correlation between TS activity and sensitivity to 5-FU. However, a weak correlation was found between DPD activity and sensitivity to 5-FU. In a subgroup of patients who did not receive adjuvant chemotherapy, overall survival was poorer in patients with high TS activity (p=0.0265). Conversely, in a subgroup of patients who received 5-FU-based adjuvant chemotherapy, overall survival was poorer in patients with high DPD activity (p=0.0465). CONCLUSION: These results suggest that TS has an important role in tumor progression and DPD may be the dominant predictor of 5-FU sensitivity in gastric cancer.

Adult↗
PubMedDate not supplied

N-hydroxyamobarbital: the second major metabolite of amobarbital in man.

After oral administration of 14C-labeled amobarbital to healthy subjects, most of the radioactivity was recovered in urine and only 4-5% in feces over a period of 6 days. No unchanged amobarbital was excreted. Two major metabolites were found and isolated. One was 3'-hydroxyamobarbital, which has been previously identified by Maynert. The second could be identified as N-hydroxyamobarbital on the basis of its spectral and chemical properties.

Amobarbital↗
PubMedDate not supplied

Catalytic and immunologic similarities between monkey and human liver cytochrome P-450db1 (human cytochrome P-450 2D6).

In vivo pharmacogenetic studies have suggested that the monkey may be an animal model for the human polymorphism of cytochrome P-450 2D6 (also called cytochrome P-450db1). In the present study, the catalytic, immunologic, and electrophoretic properties of cytochrome P-450db1 in liver microsomes from African green monkeys (Cercopithecus aethiops) were examined and compared with P-450db1 in human liver microsomes. Using sparteine as the substrate, the activity of microsomal P-450db1 from the two sources was indistinguishable in terms of the pattern of sparteine metabolites produced, the apparent Ki values of 8 competitive inhibitors (r = 0.94, p less than 0.001), and the extent of immunoinhibition by anti-rat P-450db1 antibody. Kinetic analyses demonstrated that the apparent KM values of the high affinity component of sparteine oxidation in monkey liver microsomes fell within the range observed in human livers; the Vmax of this component was as much as six times greater than the highest value reported for human liver. Western immunoblots showed a protein band in monkey liver microsomes that co-migrated with P-450db1 in human liver. The high degree of similarity observed here between P-450db1 of monkey and human liver microsomes suggests that the monkey will be a good animal model for P-450db1 enzyme studies, and possibly for studies of the role of this enzyme in drug abuse and dependence.

Animals↗
PubMedDate not supplied

N-Hydroxylation of pentobarbital in man.

After oral administration of 14C-labeled pentobarbital to healthy subjects, most ot the radioactivity was recovered in urine over a period of 6 days. Only a minute amount (approximately 1%) of unchanged pentobarbital was found in the urine. Four major metabolites were found and isolated. One was 3'-hydroxypentobarbital, which has been previously identified by Maynert. The second could be identified as N-hydroxypentobarbital on the basis of its spectral and chemical properties. The other two metabolites were not identified.

Chromatography, Thin Layer↗
PubMedDate not supplied

Cause of pregnancy-dependent mammary tumour-induced suppression of lactation in GR/A mice.

To clarify the cause of pregnancy-dependent mammary tumour (PDMT)-induced suppression of lactation due to the retardation of mammary gland growth, we studied the following: (I) mammary gland growth at the end of pregnancy in mice with PDMT [PDMT(+)] in comparison with mice without PDMT [PDMT(-)] and (II) effects of PDMT removal at the end of pregnancy on mammary gland growth and function. In Experiment I, little difference was observed between PDMT(-) and PDMT(+) groups in mammary DNA content and plasma level of lactogenic hormone or progesterone at the end of pregnancy, indicating that the retardation of mammary gland growth by PDMT does not occur during pregnancy. In Experiment II, the surgical removal of PDMT 1 or 2 days before parturition resulted in a complete restoration of mammary gland growth and lactation. All results strongly suggest that PDMT has a deleterious effect on mammary gland growth during their abrupt regression after parturition, perhaps by secreting some mammary growth inhibitory factor(s).

Adrenal Glands↗
PubMedDate not supplied

Biliary excretion of diphenylhydantoin in the rat. Time-course studies.

The role of biliary excretion in the dose-dependent elimination of diphenylhydantoin (DPH) was investigated in the rat. During 6 hr, following iv injection of 10 mg of (14-C)DPH per kg, 28% of the radioactivity was excreted in bile and following the higher dose of DPH reached a plateau and remained constant over a period of 6 hr, whereas, with the lower dose, the excretion was a first order process (half-life 165 plus or minus 34 (SE) min). When the major metabolite of DPH,5-(P-hydroxyphenyl)-5-phenylhydantoin (P-HPPH, 14-C-labeled), was administered 1 and 10 mg/kg iv), the rates of biliary excretion of total radioactivity were first order, with half-lives of 49 plus or minus 3 and 57 plus or minus 4 min, respectively. Therefore, the conjugation of p-HPPH and the transfer of the conjugate from liver cells into bile were not saturable with the two doses studied. The data are consistent with the assumption that the dose-dependent elimination of DPH is due to the saturable conversion of DPH to p-HPPH.

Animals↗
PubMedDate not supplied

Haloperidol reductase in human and guinea pig livers.

A GC assay method for haloperidol reductase was developed. Haloperidol reductase was present in guinea pig liver cytosol as well as in the microsomes, while in human liver only the cytosol exhibited the activity. The reductase activity was NADPH dependent for both species. Known substrates of ketone reductase such as menadione, daunorubicin, and ethacrynic acid strongly inhibited the human haloperidol reductase. The haloperidol reductase showed characteristics of ketone reductase.

Animals↗
PubMedDate not supplied

Evidence in humans for variant allozymes of the nondeficient sparteine/debrisoquine monooxygenase (P45OIID 1) in vitro.

Sparteine oxidation is part of a genetic polymorphism that affects the metabolism of many drugs and is under monogenic control. By examining the sparteine oxidation kinetics and the ratio of the dehydrogenated metabolites and through the use of the potent inhibitor, quinidine, two sites of metabolism were found for all 10 of the livers studied. The mean Km (N = 10) for the quinidine-sensitive enzyme is 73 +/- 46 (SD) microM and the mean Vmax is 4.51 +/- 4.16 nmol/mg microsomal protein/30 min, indicating a large interindividual variation. Because the polymorphic defect is due to at least three variants of a mRNA splicing error with consequent lack of enzyme formation [Gonzalez et al.: Nature 331, 442 (1988)], the variation that we observed in Km is most likely due to variation of allozymes from extensive metabolizer alleles. The low affinity enzyme also demonstrates a large interindividual variation, is not competitively inhibited by quinidine, and produces a higher ratio of 5-dehydrosparteine to 2-dehydrosparteine than the high affinity enzyme. This low affinity enzyme must be part of a separate enzyme system from that controlling the sparteine/debrisoquine polymorphism because of its different characteristics and the 100% frequency with which it is found in the livers. The two dehydrosparteine metabolites are thought to be formed by the spontaneous breakdown of a primary metabolite. The different ratio of these two dehydrosparteines, which was found at low and high substrate concentrations, suggests that the reactions producing the primary metabolite are different between the quinidine-sensitive and -insensitive enzymes.

Cytochrome P-450 CYP2D6↗
PubMedDate not supplied

Stimulation of mammary tumourigenesis and inhibition of uterine adenomyosis by suppressed progesterone effects in SHN mice.

It has been shown in mice that progesterone stimulates both mammary tumourigenesis and uterine adenomyosis in intact animals in the presence of normal levels of prolactin and oestrogen. From the view-point of the high dependence of progesterone upon other hormones, the effects of suppressed progesterone action on mammary and uterine lesions were studied in this paper. Subcutaneous implantation of RU 486, an antiprogesterone, enhanced preneoplastic and neoplastic mammary gland growth in SHN virgin mice associated with elevated plasma prolactin levels and continued vaginal oestrous stage. This mammary gland growth stimulated by RU 486 was arrested by additional treatment with progesterone. On the contrary, RU 486 treatment markedly suppressed the development of uterine adenomyosis, which was counteracted only by progesterone supplement for a long period in old mice. The previous and the present findings conclude that progesterone stimulates mammary tumourigenesis by acting synergistically with prolactin and oestrogen when the latter hormones are at normal levels, but it prevents tumourigenesis by acting antagonistically with high levels of prolactin and oestrogen. They further confirmed the importance of progesterone in the development of adenomyosis, while its relationship with prolactin and oestrogen is not understood so well as it is in mammary tumourigenesis.

Adenoma↗
PubMedDate not supplied

Mephenytoin metabolism in vitro by human liver.

Human liver was used in investigations of mephenytoin p-hydroxylase, the enzyme presumably responsible for the genetic polymorphism in mephenytoin metabolism. A gas chromatographic assay method was developed to measure p-hydroxylation and N-demethylation which is the other major metabolic pathway. Both reactions were localized in the microsomal fraction and required NADPH. Inhibition of p-hydroxylation by CO, SKF 525-A, and metyrapone was demonstrated. It was concluded that a form of cytochrome P-450 catalyzes the reaction. The velocity of N-demethylation in human liver did not show saturation even at 500 microM substrate concentration. The p-hydroxylation, however, followed Michaelis-Menten kinetics. The Km, determined in five different livers, ranged from 59 to 143 microM. The linearity in Eadie-Hofstee plots was consistent with the involvement of a single catalytic site.

Humans↗
PubMedDate not supplied

In vitro inhibition studies of two isozymes of human liver cytochrome P-450. Mephenytoin p-hydroxylase and sparteine monooxygenase.

Human liver preparations were used to screen various drugs for their capability of binding to mephenytoin p-hydroxylase and sparteine monooxygenase, two cytochrome P-450-catalyzed activities that are independently heritable. For this screening, any indication of competitive inhibition by the drug was interpreted as an indication of binding. Among 64 drugs and alkaloids tested, 24 compounds caused inhibition of mephenytoin p-hydroxylation but the inhibition was weak in most cases; by contrast, 40 of the 64 compounds inhibited sparteine oxidation, the inhibition being potent in many cases. The only fairly strong inhibitors of mephenytoin p-hydroxylation were the alkaloid papaverine and the monoamine oxidase inhibitors tranylcypromine and nialamide. The results of these inhibition studies confirm the independence of the two monogenic defects observed in different populations. Metabolism is possibly altered in poor metabolizers of mephenytoin with fewer drugs than in poor metabolizers of sparteine.

Alkaloids↗
PubMedDate not supplied

Biotransformation of caffeine, paraxanthine, theophylline, and theobromine by polycyclic aromatic hydrocarbon-inducible cytochrome(s) P-450 in human liver microsomes.

The microsomal metabolism of caffeine and its primary dimethylxanthine metabolites, paraxanthine, theophylline, and theobromine, was investigated in 15 different human livers, including those from two known nonsmokers and one known smoker. At least two distinct enzymes with differing substrate affinities have the potential to catalyze most methylxanthine N-demethylations and C8-hydroxylations in vitro; however, at the low methylxanthine concentrations routinely encountered in vivo, participation by the high affinity site is expected to predominate. It appears that the high affinity enzyme is a polycyclic aromatic hydrocarbon-inducible isozyme of cytochrome P-450, based on competitive inhibition by 7-ethoxyresorufin and benzo[a]pyrene, and based on a significant (p less than 0.001) correlation between 7-ethoxyresorufin-O-deethylation and methylxanthine demethylation rates. alpha-Naphthoflavone inhibited all methylxanthine demethylations in excess of 80% in two high activity livers, whereas 8-hydroxylations were generally inhibited less. Kinetic analysis of paraxanthine 7-demethylation in four different liver preparations resulted in similar Km values of 1.2 +/- 0.5 mM (mean +/- SD), whereas Vmax values varied 8-fold, compatible with participation by the same high affinity isozyme. Notable was the high degree of inter-liver variation in metabolic rates, with the known smoker showing the second highest activity among a 20-fold range in paraxanthine demethylation rates, consistent with polycyclic aromatic hydrocarbon-related enzyme induction. Maximal inhibition of paraxanthine 8-hydroxylation by alpha-naphthoflavone left similar residual activities in the 15 liver preparations, indicating the presence of an enzyme activity that was not inducible. Furthermore, in low activity livers, more than 80% of paraxanthine 8-hydroxylation was mediated by an isozyme of cytochrome P-450 insensitive to inhibition by alpha-naphthoflavone. Our in vitro data show that the proportion of demethylation relative to hydroxylation products of paraxanthine correlate with 7-ethoxyresorufin O-deethylation rates. Taken together, the data provide a rationale for a potential in vivo marker of polycyclic aromatic hydrocarbon-inducible cytochrome P-450 activity based on a urinary metabolite ratio of paraxanthine 7-demethylation to 8-hydroxylation products after caffeine intake.

Adult↗
PubMedDate not supplied

Metabolism of diazepam in vitro by human liver. Independent variability of N-demethylation and C3-hydroxylation.

The interindividual variability of diazepam metabolism was studied using human livers. The formation of N-desmethyldiazepam (NDZ) and 3-hydroxydiazepam (temazepam, TMZ), was monitored by gas chromatography. In 10 livers, Km values for NDZ and TMZ formation varied independently from each other, each by a factor of 4, from 100 to 400 microM. This variability is consistent with the presence of at least two different cytochrome P-450 species controlling formation of these metabolites. In the same livers, Vmax for NDZ and TMZ production varied 6-fold and 15-fold, respectively.

Anti-Anxiety Agents↗