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Biomedical subjects

T Shimada

Publications and source records attributed to T Shimada.

At least 343 records · Page 19Linked to original sources
PubMed1998

[Primary non-Hodgkin's lymphoma of the uterine cervix complicated by acute renal failure due to ureter obstruction].

An 80-year-old woman was referred to our hospital because of irregular genital bleeding. An abnormal mass was found in the uterine cervix, and diagnosed as non-Hodgkin's lymphoma, diffuse large B cell type. Soon after admission, the patient became anuric and was given a diagnosis of acute renal failure due to obstruction of the ureter. She was immediately placed on dose-reduced CHOP and radiotherapy of 15 Gy. As a result, not only did the malignant lymphoma go into remission, but diminished renal function was alleviated. Because malignant lymphoma of the uterus is extremely rare, it exact biocharacteristics are not well understood. We are unaware of any previous report concerning uterine lymphoma complicated by renal failure.

Acute Kidney Injury↗
PubMed1998

[Cytokines and gut].

Cytokines are soluble proteins or glycoproteins produced by a wide variety of cell types. Cytokines are local regulatory factors which are involved in cell growth, cell differentiation, inflammation, and immune responses. In the gastrointestinal mucosa, not only inflammatory cells but also epithelial and mesenchymal cells secrete cytokines in response to various stimuli. Inflammatory cytokines are playing critical roles in the inflammation associated with gastrointestinal infections, including Helicobacter pylori infection in the gastric mucosa. Animal studies have shown that abnormal cytokine response may be risk for developing inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. Cytokines will be important therapeutic targets in these diseases.

Animals↗
PubMed1998

[Immunohistochemical studies in depressed type adenomas of the stomach--comparison with protruded type adenomas and depressed type well differentiated mucosal gastric cancers].

In this study, we performed immunohistochemical studies using p53 and Ki-67 immunostaining in 48 depressed type adenomas, and compared with protruded type adenomas (n = 28) and depressed type well differentiated mucosal gastric cancers (mcancer: n = 46). Focal and diffuse p53 staining patterns were not noticed in depressed type adenomas and in protruded type adenomas, but were noticed in mcancers (focal: 4.3%, diffuse: 41.3%). Ki-67 positive cells were noticed in surface epithelium in 24.4% of depressed type adenomas, in 21.4% of protruded type adenomas and in 87.0% of mcancers. Ki-67 positive rate in foveolar epithelium (superior, middle, inferior) were noticed in (31.1%, 12.9%, 6.1%) of depressed type adenomas, in (33.4%, 15.4%, 6.9%) of protruded type adenomas and in (33.4%, 31.4%, 20.4%) of mcancers. These results suggest that from the point of immunohistochemistry, depressed type adenomas were similar to protruded type adenomas, but were different from mcancers.

Adenoma↗
PubMed1998

Obstructive jaundice due to multiple hepatic abscesses.

A 63-year-old Japanese male with diabetes mellitus developed obstructive jaundice following the onset of multiple hepatic abscesses. Percutaneous transhepatic cholangiography showed intrahepatic bile duct irregularity and dilatations accompanied by a complete obstruction of the right branch of the intrahepatic bile duct. Three kinds of organisms were cultured from the blood and the drained bile. The cholangiographic changes returned to the normal after the liver abscesses subsided following biliary drainage and the administration of intravenous antibiotics.

Bacteroides Infections↗
PubMed1998

Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6beta-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin.

Roxithromycin has been shown to be a relatively weak inhibitor of cytochrome P450 (P450 or CYP)-dependent drug oxidations, compared with troleandomycin. The potential for roxithromycin and its major metabolites found in human urine [namely the decladinosyl derivative (M1), O-dealkyl derivative (M2), and N-demethyl derivative (M3)] to inhibit testosterone 6beta-hydroxylation after metabolic activation by CYP3A4 was examined and compared with inhibition by troleandomycin and erythromycin in vitro. Of roxithromycin and its studied metabolites, M3 was the most potent in inhibiting CYP3A4-dependent testosterone 6beta-hydroxylation by human liver microsomes and was activated to the inhibitory P450.Fe2+-metabolite complex to the greatest extent. Roxithromycin and its metabolites were N-demethylated by human liver microsomes, although the rates were slower than those measured with troleandomycin and erythromycin as substrates. Recombinant human CYP3A4 in a baculovirus system coexpressing NADPH-P450 reductase was very active in catalyzing the N-demethylation of roxithromycin, M1, and M2, as well as troleandomycin, erythromycin, and M3. The order for inhibition of CYP3A4-dependent testosterone 6beta-hydroxylation activities by these macrolide antibiotics in the recombinant CYP3A4 system was estimated to be troleandomycin > erythromycin >/= M3 >/= M2 > M1 >/= roxithromycin. Erythromycin, roxithromycin, and its metabolites all failed to inhibit CYP1A2-dependent (R)-warfarin 7-hydroxylation and CYP2C9-dependent (S)-warfarin 7-hydroxylation but did inhibit CYP3A4-dependent (R)-warfarin 7-hydroxylation. These results suggest that roxithromycin itself is not as potent an inhibitor of CYP3A4 activities as are troleandomycin and erythromycin, probably because of the slower metabolism of this compound to metabolites M1, M2, and M3 in humans.

Anti-Bacterial Agents↗
PubMed1998

[A successful case report on intralesional OK-432 therapy for cystic mediastinal lymphangiomas].

A 42-years-old female was referred to the university hospital because of cystic lesions of the right superior mediastinum. Drainage tube was found at right supraclavicular fossa with prolonged lymphatic discharge. We diagnosed this case as a benign cystic lymphangiomas with CT scan and CT scan with cystography and chemical analysis of the contents of the cyst. Intralesional OK-432 therapy for cystic mediastinal lymphangioma was performed. OK-432 was administered through intralesionally placed drainage tube. Excellent result was obtained. A few weeks later, residual lymphatic discharge through drainage tube became stopped. No expansion of the mediastinal cyst was found after drainage tube removal. Intralesional OK-432 therapy for cystic mediastinal lymphangioma was very effective and useful, it should be recommended for the management of the first choice of therapeutic method for cystic mediastinal lymphangioma because of no neurological deficit after this treatment.

Adult↗
PubMed1998

[Waldenström's macroglobulinemia effectively treated with chronic daily oral administration of low-dose etoposide].

A 77-year-old woman with complaints of fever and systemic lymphadenopathy was admitted to our hospital on February 16, 1995. Serum IgM was elevated to 2,097 mg/dl. Lymph node biopsy showed diffuse infiltration with lymphoplasmacytoid cells. Thus, she was diagnosed as having Waldenström's macroglobulinemia. Considering her age and congestive heart failure, she was treated with oral administration of low-dose etoposide (25 mg/day). Splenomegaly and superficial lymphadenopathy disappeared after one course of therapy. Until her death due to pneumonia, complete remission continued for one year without any symptoms and adverse effects except for mild diarrhea. Low-dose etoposide therapy was considered to be well tolerated and useful for elderly patients with Waldenström's macroglobulinemia.

Administration, Oral↗
PubMed1998

Twenty years of biochemistry of human P450s: purification, expression, mechanism, and relevance to drugs.

Today cytochrome P450 (P450) research is accepted as an integral part of drug development and discovery. Work leading to this point included biochemical studies on P450 in experimental animal models and application to human systems. The development of recombinant expression systems has been an important part of the progress, and in this article we describe some recently developed bacterial systems that can be used for the production of metabolites, genotoxicity testing, and screening in random mutagenesis work. Rate-limiting aspects of P450 reactions vary with particular systems, and further investigations are in order. Non-ionic detergents have been utilized widely in P450 purification work; these compounds are now shown to be substrates for P450s. These oxidations are not only of fundamental interest in expanding the repertoire of P450 substrates but have significance in light of human exposure to these compounds.

Cytochrome P-450 Enzyme System↗
PubMed1998

The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel.

Desogestrel is a 3-deoxo progestogenic steroid that requires bioactivation to 3-ketodesogestrel. In these studies we have attempted to define the pathway of 3-ketodesogestrel formation and characterise the enzymes responsible for this biotransformation in vitro. Initial studies using deuterated desogestrel confirmed that desogestrel is metabolised by human liver microsomes via 3alpha-hydroxy and 3beta-hydroxydesogestrel to 3-ketodesogestrel. Metabolites were analysed by radiometric high-performance liquid chromatography and were identified by liquid chromatography-mass spectrometry and by cochromatography with authentic standards. Desogestrel was metabolised by microsomes from lymphoblasts containing cDNA-expressed CYP2C9 and CYP2C19 to 3alpha-hydroxydesogestrel with small amounts of 3beta-hydroxydesogestrel also being observed. The Km value for 3alpha-hydroxylation by CYP2C9 cell line microsomes was 6.5 microM and the corresponding Vmax value was 1269 pmole. mg-1. min-1. Sulfaphenazole potently inhibited 3alpha-hydroxydesogestrel formation by CYP2C9 microsomes with a Ki value of 0.91 microM. There was a significant negative correlation between 3-ketodesogestrel and CYP3A4 content/activity in a panel of human livers suggesting that the further metabolism of 3-ketodesogestrel is mediated by CYP3A4. Sulfaphenazole partially inhibited 3alpha-hydroxydesogestrel and 3-ketodesogestrel formation in human liver microsomes indicating a possible in vivo role for CYP2C9. In addition, when sulfaphenazole was combined with S-mephenytoin, further inhibition of 3alpha-hydroxydesogestrel formation was observed suggesting a possible role for CYP2C19. This was confirmed in incubations with inhibitory antibodies. Whereas an anti-CYP2C9/2C19 antibody completely abolished desogestrel metabolism, anti-CYP3A4 and anti-CYP2E1 were not inhibitory. We conclude that CYP2C9 and possibly CYP2C19 and important isoforms catalysing the initial hydroxylation of desogestrel.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers.

Human liver microsomes had about 8-fold higher 7-hydroxylation activities for S-warfarin than for R-warfarin. Activities of racemic warfarin 7-hydroxylation by liver microsomes of 35 human samples correlated more closely with those of S-warfarin 7-hydroxylation (r = 0.95) than with those of R-warfarin 7-hydroxylation (r = 0.69). The correlation coefficient between R-warfarin 7-hydroxylation and 7-ethoxyresorufin O-deethylation activities was 0.73 in these human samples, suggesting that R- and S-warfarin enantiomers are catalyzed by different forms of human cytochrome P450 (P450 or CYP) enzymes. Anti-CYP2C9 antibodies inhibited completely the 7-hydroxylation of S-warfarin, but not R-warfarin, catalyzed by human liver microsomes, while anti-CYP1A2 inhibited R-warfarin 7-hydroxylation by about 70%. Interestingly, the racemic warfarin 7-hydroxylation activities (turnover numbers of 1.6 +/- 1.0 pmol/min/mg protein in 35 human samples) were found to be low compared with the S-warfarin 7-hydroxylation activities (4.1 +/- 2.5 pmol/min/mg protein), indicating that R-warfarin may have affected the CYP2C9-dependent S-warfarin 7-hydroxylation activities when racemic warfarin was used as a substrate. Several P450 inhibitors, as well as R-warfarin, were examined for their abilities to inhibit S-warfarin 7-hydroxylation; we found that R-warfarin was a non-competitive inhibitor with a Ki value of about 150 microM, whereas both tolbutamide and sulfaphenazole were competitive inhibitors with Ki values of about 100 and 0.5 microM, respectively, for S-warfarin 7-hydroxylation activities. These results suggest that R- and S-warfarin enantiomers are catalyzed principally by CYP1A2 and CYP2C9, respectively, in human liver microsomes, and that the pharmacokinetic properties of S-warfarin may be altered by R-warfarin in vivo when racemic warfarin is administered clinically to humans.

Animals↗
PubMed1997

The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains.

Mouse Tabby (Ta) and X chromosome-linked human EDA share the features of hypoplastic hair, teeth, and eccrine sweat glands. We have cloned the Ta gene and find it to be homologous to the EDA gene. The gene is altered in two Ta alleles with a point mutation or a deletion. The gene is expressed in developing teeth and epidermis; no expression is seen in corresponding tissues from Ta mice. Ta and EDA genes both encode alternatively spliced forms; novel exons now extend the 3' end of the EDA gene. All transcripts recovered have the same 5' exon. The longest Ta cDNA encodes a 391-residue transmembrane protein, ectodysplasin-A, containing 19 Gly-Xaa-Yaa repeats. The isoforms of ectodysplasin-A may correlate with differential roles during embryonic development.

Alternative Splicing↗
PubMed1997

Alanine scanning mutagenesis of the switch I region in the ATPase site of Dictyostelium discoideum myosin II.

In order to determine the functional roles of the conserved sequence (NXNSSRFG) of the "switch I" loop (residues 233-240 in Dictyostelium myosin II), alanine scanning mutagenesis was performed on Dictyostelium myosin II. N233A and S237A mutant myosins did not bind a fluorescent analog of ADP, mant-deoxyADP, at the low concentration range (micromolar and had low level of ATPase activities. They were nonmotile when examined by the in vitro motility assay. Dictyostelium cells expressing these myosins showed worse phenotypes than that of myosin-null cells. In contrast to these mutant myosins, R238A myosin tightly bound mant-deoxyADP. However, the mutant had a defect in the ATP hydrolysis step and exhibited the lowest ATPase activities among the mutants examined here. The R238A myosin was nonmotile. R238C or R238H mutations, which mimic the Usher syndrome mutations, generated myosins with similar functional defects to those of the R238A mutation. Cells expressing the R238A myosin exhibited the phenotype similar to that of the myosin-null cells. N235A, S236A, F239A, and G240A myosins retained moderate levels of ATPase activities and could drive sliding of actin filaments at various speeds. Phenotypes of cells expressing them were very similar to that of the wild-type cells. Taken together, these results suggest that side chains of N233 and S237 may play essential roles in holding a nucleotide in the ATPase pocket and that R238 may play crucial roles in the ATP hydrolysis step, while those of the other residues in the switch I loop are not essential for the process.

Adenosine Diphosphate↗
PubMed1997

Inhibition of human cytochrome P450-catalyzed oxidations of xenobiotics and procarcinogens by synthetic organoselenium compounds.

The effects of synthetic chemopreventive organoselenium compounds 1,2-, 1,3-, and 1,4-phenylenebis(methylene)selenocyanate (o-, m-, and p-XSC, respectively), benzyl selenocyanate (BSC), and dibenzyl diselenide (DDS) and inorganic sodium selenite on the oxidation of xenobiotics and procarcinogens by human cytochrome P450 (P450 or CYP) enzymes were determined in vitro. Spectral studies showed that BSC and three XSC compounds (but not sodium selenite or DDS) induced type II difference spectrum when added to the suspension of liver microsomes isolated from beta-naphthoflavone-treated rats, with m-XSC being the most potent in inducing spectral interactions with P450 enzymes; m-XSC also produced a type II spectral change with human liver microsomes. o-, m-, and p-XSC inhibited 7-ethoxyresorufin O-deethylation catalyzed by human liver microsomes when added at concentrations below 1 microM levels, but BSC and DDS were less effective. All of these compounds inhibited the oxidation of model substrates for human P450s to varying extents. We studied the effects of these compounds on the activation of procarcinogens by recombinant human CYP1A1, 1A2, and 1B1 enzymes using Salmonella typhimurium NM2009 tester strain for the detection of DNA damage. The three XSCs were found to be very potent inhibitors of metabolic activation of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-amino-3,5-dimethylimidazo[4,5-f]quinoline, and 2-aminoanthracene, catalyzed by CYP1A1, 1A2, and 1B1, respectively. The potency of inhibition of m-XSC on CYP1B1-dependent activation of 2-aminoanthracene was compatible to those of alpha-naphthoflavone. These inhibitory actions may, in part, account for the mechanisms responsible for cancer prevention by organoselenium compounds in laboratory animals.

Animals↗
PubMed1997

Expression of cytochrome P450 3A7 in Escherichia coli: effects of 5' modification and catalytic characterization of recombinant enzyme expressed in bicistronic format with NADPH-cytochrome P450 reductase.

Cytochrome P450 3A7 is the major P450 form present in fetal liver tissue and may be responsible for the detoxification of many drugs that reach the fetal circulation. We report the development of bacterial expression systems for P450 3A7. Maximal yields (up to 50 nmol P450/liter culture) were obtained with a construct in which the 5'-terminus of the 3A7 cDNA was modified to include the MALLLAVFL N-terminal sequence of recombinant bovine P450 17A (H. J. Barnes, M. P. Arlotto, and M. R. Waterman, Proc. Natl. Acad. Sci. USA 88, 5597-5601, 1991) and to incorporate several downstream amino acid substitutions derived from the P450 3A5 sequence. This sequence also appeared optimal for expression of P450 3A4 and 3A5. Recombinant P450 3A7 was partially purified using ion-exchange and hydroxylapatite chromatography and reconstituted with NADPH-cytochrome P450 reductase, cytochrome b5, and lipids. Activity comparable to that of P450 3A4 was demonstrated toward a number of procarcinogens. An alternative approach was used to further characterize recombinant 3A7 due to low yields of recombinant protein in the expression and poor recovery in the purification. P450 3A7 was subcloned into a bicistronic vector containing human NADPH-cytochrome P450 reductase and expressed in bacteria. Recombinant P450 3A7 coexpressed in bacterial membranes with NADPH-cytochrome P450 reductase showed similar levels of activity toward erythromycin (N-demethylation) and ethylmorphine (N-demethylation) to P450 3A4 and 3A5 expressed in the same system, whereas 3A7 was less active toward midazolam (1'- and 4-hydroxylation) and nifedipine (oxidation).

Amino Acid Sequence↗
PubMed1997

Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes.

Roles of human cytochrome P450 (P450 or CYP) 2C9, 2C19, and 3A4 in the oxidation of progesterone and testosterone were studied in recombinant P450 enzymes and in human liver microsomes. In vitro inhibition experiments showed that progesterone and its 17alpha- and 21-hydroxylated metabolites and 11-deoxycortisol suppressed the CYP2C19-dependent R-warfarin 7-hydroxylation activities, with progesterone being the most active. These steroid chemicals also inhibited CYP2C9-dependent S-warfarin 7-hydroxylation activities though lesser extents seen with those in CYP2C19 enzyme. Progesterone was found to be a competitive inhibitor of CYP2C19 and CYP2C9 in human liver microsomes. Recombinant CYP2C19 catalyzed progesterone to form 21-hydroxyprogesterone as a major product and 16alpha- and 17alpha-hydroxyprogesterone as minor products. CYP2C9 also had progesterone 21-hydroxylation activities, although the activities were lower than those catalyzed by CYP2C19. Vmax/Km ratios for the progesterone 21-hydroxylation activity of CYP2C19 were determined to be 13- and 32-fold higher than those of CYP2C9 and 3A4, respectively. CYP3A4 oxidized progesterone to form 16alpha-, 6beta-, and 2beta-hydroxyprogesterone as major products and 21-hydroxyprogesterone as a minor product, but did not produce detectable levels of 17alpha-hydroxyprogesterone. Immunoinhibition experiments suggested that anti-CYP2C9 (which inhibits both CYP2C9 and CYP2C19 catalytic activities) suppressed the progesterone 21-hydroxylation activities catalyzed by liver microsomes of humans and monkeys and that anti-CYP2C11 inhibited the progesterone 21-hydroxylation activities catalyzed by liver microsomes of male rats. CYP2C19 was also found to oxidize testosterone at 17-position to form androstenedione. Androstenedione formation catalyzed by liver microsomes of humans and monkeys and of male rats was suppressed by anti-CYP2C9 and anti-CYP2C11, respectively. These results suggest that CYP2C19 plays important roles in the oxidation of progesterone and testosterone in human liver microsomes, although the physiological significance of these metabolic pathways remains unclear. CYP2C9 may have some, but lesser extent than those by CYP2C19, of the catalytic roles for the metabolism of progesterone and testosterone by human liver microsomes.

Androstenedione↗