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T Yanase

Publications and source records attributed to T Yanase.

At least 109 records · Page 6Linked to original sources
PubMed1994

In-vitro evidence for the regulation of 17,20-lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome.

OBJECTIVE: The electron transfer system molecules, NADPH-cytochrome P450 reductase (Red) and cytochrome b5 (b5) are known to increase the relative activity of 17,20-lyase to 17 alpha-hydroxylase in vitro. Consistent with this hypothesis, we have reported recently that adrenocortical adenomas from patients with Cushing's syndrome that produced exceptionally high concentrations of androgens also contained more b5 mRNA as well as greater 17,20-lyase activity than adenomas that produced low concentrations of androgens. This finding was suggestive but inconclusive in linking b5 functionally to this difference in adenoma 17,20-lyase activity. In the present study, we have extended this finding by examining the effect of b5 on microsomal 17,20-lyase activity using an antibody against cytochrome b5. DESIGN: Biochemical quantitation of the content of b5 and Red activity in the microsomal fraction of the tumours and determination of 17,20-lyase activity in the microsomes in the presence or absence of an antibody against b5. PATIENTS: Seven patients with a clinical diagnosis of Cushing's syndrome secondary to benign adrenocortical adenoma were studied. MEASUREMENTS: The microsomal activities of 17 alpha-hydroxylase, 17,20-lyase and 3 beta-hydroxysteroid dehydrogenase were measured by in-vitro enzyme assay with thin layer chromatography. Microsomal Red activity was assayed by measuring NADPH-dependent cytochrome c reduction reaction. Cytochrome b5 concentration was determined by spectrophotometric analysis. RESULTS: An in-vitro enzyme assay of microsomal fractions from the adenoma showed that the 17,20-lyase activities of two adenomas that produced high concentrations of adrenal androgen were threefold greater than those of five other adenomas that produced low concentrations of androgens. Cytochrome b5 concentrations were greater in the two adenomas with high 17,20-lyase activity than in the other adenomas, while no significant difference in Red activity was observed among all the adenomas. The increased 17,20-lyase activity in the two adenomas was partially but significantly antagonized by an antibody against b5. CONCLUSIONS: These results suggest that differences in tissue b5 are functionally associated with differences in 17,20-lyase activity in adrenocortical adenomas in Cushing's syndrome, resulting in a dissociated secretion of cortisol and androgens in some patients.

Adenoma↗
PubMed1994

Mechanism of abnormal production of adrenal androgens in patients with adrenocortical adenomas and carcinomas.

The production of adrenal androgens can be modulated by the activities of steroidogenic enzymes and by the electron transfer system, NADPH-cytochrome P450 reductase (Red) and cytochrome b5 (b5), both of which have been shown to increase 17,20-lyase activity in vitro. To clarify the mechanism of diminished secretion of adrenal androgens in patients with adrenocortical adenoma and Cushing's syndrome and of excess secretion in patients with adrenocortical carcinoma, we investigated the enzymatic activities of cytochrome P45017 alpha, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), and Red as well as the content of b5 in five adenomas, three carcinomas, and two normal adrenal glands. An in vitro enzyme assay using a microsomal fraction of the tissues indicated that all the tumors had almost the same degree of 17 alpha-hydroxylase activities as the normal adrenals. However, the relative activity ratio of 17,20-lyase to 17 alpha-hydroxylase of the three adenomas was markedly diminished, and 3 beta-HSD activity was apparently lower in the three carcinomas. The messenger RNA concentrations of P45017 alpha were similar in all tumors, whereas those of 3 beta-HSD were markedly lower in the carcinomas than in other tissues. Both the content of b5 and the activity of Red were significantly lower in the adenomas. These results suggest that low concentrations of adrenal androgens in patients with adrenocortical adenomas are mainly due to low 17,20-lyase activity, which may be explained in part by a lower content of b5 and Red. In addition, high concentrations of adrenal androgens in patients with adrenocortical carcinoma are mainly due to the diminished activity of 3 beta-HSD.

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

No mutation in cytochrome P450 side chain cleavage in a patient with congenital lipoid adrenal hyperplasia.

Molecular basis of lipoid adrenal hyperplasia (lipoid CAH) in a Japanese patient was investigated. A 46XY Japanese female patient was clinically diagnosed as having lipoid CAH based on her clinical history of adrenal crisis at birth and the low basal concentrations of cortisol, aldosterone, adrenal androgens and testosterone in serum. In vitro studies of testicular mitochondrial enzymes confirmed a specific impairment of cholesterol side chain cleavage (SCC) activity. However, in spite of the virtual reduction of SCC activity, the amounts of immunodetectable P450scc, adrenodoxin reductase, and adrenodoxin in testicular mitochondria were almost same as those of normal testis. Furthermore, the size of each protein was similar to that of normal testis. Enzymatic amplification of the complementary DNA encoding P450scc from the patient's testis RNA and its nucleotide analysis by direct sequencing revealed no mutation. These results indicate that defective P450scc is not the lesion in this patient, confirming a previous report showing no P450scc mutations in patients with lipoid CAH. The exact lesion causing lipoid CAH in this patient is currently unknown.

Adolescent↗
PubMed1994

Catechol estrogens are more potent antioxidants than estrogens for the Cu(2+)-catalyzed oxidation of low or high density lipoprotein: antioxidative effects of steroids on lipoproteins.

In order to clarify the mechanism of antiatherogenic action of several steroids such as estrogens, dehydroepiandrosterone (DHEA) and dexamethasone, we investigated the effects of various steroids on the copper (Cu2+)-catalyzed oxidation of low density lipoprotein (LDL) or high density lipoprotein (HDL) in 0.15 M NaCl by measuring thiobarbituric acid-reactive substances (TBARS). At a concentration of 10(-5) M, estrogens strongly protected against LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: estradiol (E2) (75%), estrone (E1) (35%) and estriol (E3) (30%). However, the corresponding metabolites of these estrogens, the catechol estrogens, had an even more protective effect on LDL oxidation by 0.5 microM Cu2+ in the following order of inhibition: 2-hydroxyestradiol (2-OHE2) (98%), 2-OHE1 (97%) and 2-OHE3 (96%). E2 and 2-OHE2 from 10(-7) M to 10(-5) M inhibited LDL oxidation in a dose-dependent manner, with a more marked effect for oxidation by 0.1 microM Cu2+ than by 0.5 microM Cu2+. 10(-5) M dexamethasone produced a slight (10%) but significant inhibition of LDL oxidation by 0.5 microM Cu2+. In addition, the estrogens and catechol estrogens were also effective in protecting against HDL oxidation by 0.5 microM Cu2+. Other steroids including DHEA and DHEA-sulfate had no antioxidative effects on either LDL or HDL in this system. These results indicate that estrogens and their metabolites, the catechol estrogens, exert antioxidative effects on both LDL and HDL. The catechol estrogens may be more important antioxidants than estrogens for both LDL and HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Antioxidants↗
PubMed1994

Age-related increase in neuropeptide Y-like immunoreactivity in cerebrospinal fluid in women.

In order to investigate the age-related changes in neuropeptide Y (NPY) in cerebrospinal fluid (CSF) of men and women, we examined the concentration of NPY-like immunoreactivity (NPY-LI) in CSF of a large population of Japanese men and women by specific radioimmunoassay (RIA). The dilution curve of CSF extract paralleled the standard curve of RIA for human NPY. Gel chromatographic studies revealed the presence of two peaks of NPY-LI, one emerging at the elution position of synthetic NPY and another emerging at a higher-molecular-weight position. NPY-LI in the CSF in 201 men (aged 17 to 69y) and 118 women (aged 17 to 69y) was 124 +/- 4 and 136 +/- 6 pg/ml (mean +/- SE), respectively. NPY-LI in the CSF of women, but not of men, increased significantly with aging. This finding suggests that the level of NPY with aging in the central nervous system (CNS) may be regulated somewhat differently in men and women.

Adolescent↗
PubMed1994

[A case of adrenal pheochromocytoma with normotention and normal levels of urinary excretion of catecholamines].

A 62-year-old man was admitted to our hospital for further examination of right adrenal mass accidentally pointed out by ultrasonogram. He had no symptoms and no physiological abnormalities. Endcrinological examinations revealed normal adrenocortical function, excluding the possibility of functioning adrenocortical adenoma. Pheochromocytoma seemed to be also unlikely since 24-hr urinary excretion of catecholamines were within normal limits. The tumor was surgically removed and histopathologically diagnosed as pheochromocytoma. This case of adrenal incidentaloma is unique in that little sign of pheochromocytoma was presented before operation. The reasons were discussed especially in respect of tissue contents of catecholamines and opioid peptide in comparison with other cases with pheochromocytoma we had experienced.

Adrenal Gland Neoplasms↗
PubMed1994

A point mutation in the bile acid biosynthetic enzyme sterol 27-hydroxylase in a family with cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare familial disorder characterized by progressive neurological dysfunction, atherosclerosis, and xanthomas with sterol storage in the nervous system, vessels, and tendons. Increased serum cholestanol, derived from intermediates of cholesterol catabolism, may possibly be a major cause of the disease. An examination was made of the cDNA encoding cytochrome P450 sterol 27-hydroxylase (CYP27) in hepatic mitochondria, considered a defective enzyme inducing CTX, in a Japanese housewife afflicted with CTX and her family. The proposita and one of her brothers, who also had CTX symptoms and hypercholestanolemia, were found to be homozygotic, carrying a point mutation in the CYP27 gene at Arg104 (CGG) to Trp104 (TGG). The mutant position has a 100% conserved positive charge in all known vertebrate cytochrome P450s and even in bacterial cytochrome P450cam. The mother of the proposita and another brother were both free of CTX symptoms and were heterozygotic for the mutation, although their plasma cholesterol increased moderately. An increase in plasma cholestanol alone would, thus, not appear to be a direct cause of sterol storage in CTX, while CTX is strongly suggested to be caused by defects in both alleles of the CYP27 gene.

Aged↗
PubMed1994

Reserved Sertoli cell function in the hypogonadic male patients with myotonic dystrophy.

To clarify the Sertoli cell and Leydig cell function in hypogonadic male patients with myotonic dystrophy (DM), serum concentrations of inhibin, total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay in 6 male DM patients (41 to 56 years old, 47.7 +/- 5.05 years old) and compared with those in normal adult men. In 116 healthy men aged from 24 to 92 years, serum inhibin and TT levels decreased and serum FSH and LH concentrations increased with advancing age. There was an inverse correlation between serum inhibin and FSH. These results support the concept of negative feedback regulation system of FSH secretion by inhibin. Male DM patients showed significantly lower serum TT and higher concentrations of FSH and LH, compared with the age-matched 39 normal adult men (49-59 years old, 48.2 +/- 6.14 years old). However, there was no significant difference in serum inhibin levels between the patients and normal counterparts. These results indicate that the Sertoli cell function is reserved in male DM patient, although the Leydig cell function is impaired. It is also suggested that in these patients a negative feedback control system between inhibin and FSH may be disordered to some extent.

Adult↗
PubMed1994

An important role of glomerular segmental lesions on progression of IgA nephropathy: a multivariate analysis.

The independent predictors of progression of IgA nephropathy (IgAN) were investigated by multivariate life table analysis, using Cox's proportional hazard model, in 225 patients with IgAN diagnosed by renal biopsy (Bx). There were 105 men and 120 women. Mean age at Bx was 32.5 years. The follow-up period following Bx was 4.0 +/- 2.6 yrs, ranging from 5 months to 11 yrs. The clinical parameters analyzed were age at the time of discovery of the disease, age at Bx, intervals from discovery to Bx, presence or absence of macrohematuria, and clinical data at Bx such as presence or absence of hypertension, the degree of hematuria, the amount of urinary protein excretion, serum creatinine and serum IgA concentration. The following immunopathological parameters were also examined; glomerular hypercellularity index, percentage of glomeruli associated with segmental lesions such as tuft adhesions, crescents and segmental sclerosis, percentage of obliterated glomeruli by global sclerosis, severity of interstitial infiltration, fibrosis, arterial wall thickening, arterial hyaline changes, and intensity of the depositions of IgG, IgA, IgM, C3, C1q and fibrinogen by immunofluorescent study. Among all clinical and pathologic parameters examined, the following parameters were proved to be significant independent predictors of progression of IgAN: serum creatinine exceeding 1.5 mg/dl in men and 1.3 mg/dl in women, proteinuria over 2 g/day, segmental lesions involving more than 25% of glomeruli and interstitial fibrosis occupying more than 25% of cortical area.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Clinicopathological study of poststreptococcal glomerulonephritis in the elderly.

In order to characterize the clinical features in elderly patients with poststreptococcal glomerulonephritis (PSGN), 31 patients, who were both histologically and immunologically proven to be PSGN, were divided up into 3 groups according to age; elderly patients being 55 years or older (n = 7), middle-aged patients being 40 to 54 years old (n = 7) and younger patients being 20 to 39 years old (n = 17). Renal functional impairment as indicated by serum creatinine levels of over 2.0 mg/dl, developed in 4 of the elderly patients and later completely improved at the end of the follow-up period (178.9 +/- 150.7 days). On the other hand, none of the middle-aged and younger patients revealed any renal function impairment. Hypertension was observed more frequently in elderly patients than in younger patients, and was 86% and 6% at the time of admission, respectively. In addition, 43% of elderly patients remained hypertensive at the time of discharge. There was no difference in total protein, ASO, CH50, the degree of proteinuria or proliferative and exudative features in renal histology among the three groups. None of the elderly patients with PSGN died or developed persistent renal failure. In conclusion, elderly patients with PSGN had a high incidence of renal functional impairment and hypertension compared to the younger patients on admission, however, their short-term prognosis seems to be favorable.

Adult↗
PubMed1994

[Clinical evaluation of granisetron injection against nausea and vomiting induced by anticancer drugs including cisplatin].

The antiemetic effect and safety of granisetron injection on nausea and vomiting induced by anticancer drugs were studied in the patients treated with anticancer drugs including 50 mg/m2 or more of cisplatin (CDDP). Granisetron is already on the market, and drip infusion of granisetron at 40 micrograms/kg has been used widely in clinical practice. In this clinical investigation, a simpler administration method of its slow (30 to 60 seconds) intravenous injection at 40 micrograms/kg just before CDDP administration was used. The clinical efficacy, safety and usefulness against nausea and vomiting were investigated in 22 patients, and the study medication was assessed as "remarkably effective" or "effective" in 16 patients (72.7%). Neither adverse experience nor abnormal laboratory test value was reported. In the usefulness rating, the study medication was assessed as "extremely useful" or "useful" in 16 out of 22 patients (72.7%). The above results have shown that the slow intravenous injection of granisetron has an excellent antiemetic effect on nausea and vomiting induced by anticancer drugs including CDDP and a high degree of safety.

Adult↗
PubMed1994

[Action mechanism of synthetic glucocorticoids].

Molecular and cellular mechanisms of glucocorticoids (GCs) action and the effects of GCs have been briefly reviewed. GCs exert their effect by binding to GC receptor, which are direct modulators of gene transcription. GC receptor is a member of steroid receptor superfamily and consists of several functional domains including DNA binding and hormone binding. GC receptor was first shown to be a potent activator of transcription, but recently, GC receptor has also been shown to repress expression of various of genes through interaction with other transcriptional factors. GC has a variety of physiological and pharmacological effects on carbohydrate and lipid metabolism, immunological functions and inflammatory processes, fluid and electrolyte homeostasis, bone and mineral metabolism, musculoskeletal tissues and so on. The details of these effects have been described.

Animals↗
PubMed1993

Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo.

Antitumor activity of angiogenesis inhibitor TNP-470 was evaluated in eight human cultured cell lines derived from choriocarcinoma: SCH, NUC-1, and GCH-1(m); ovarian cancer; TYK and Nakajima; and uterine endometrial cancer: HEC-6, HEC-50, and HEC-1-A. After 7-day culture with TNP-470, in medium at the concentration of 10(1) to 10(-2) micrograms/ml, the inhibition of growth was observed in all of the eight cell lines. The 50% inhibitory concentration of choriocarcinona cell lines was at an extremely low level compared to that of epithelial ovarian cancer and uterine endometrial cancer. In addition, the antitumor effect of this compound was studied in in vivo experiments using nude mice with tumors of GCH-1(m), NUC-1, or Nakajima cells. When the size of the transplanted tumor reached 100-200 mm3 in volume, 3, 10, or 30 mg/kg of TNP-470 was injected s.c. every other day. The inhibitory effect of TNP-470 was obtained by the administration of 10 and 30 mg/kg in GCH-1(m) and NUC-1 cells, respectively, while in Nakajima cells no significant effect was observed. In nude mice treated with 30 mg/kg of TNP-470, lung metastasis of GCH-1(m) cells was strongly inhibited both in the number and in the size of tumor nodules, indicating that the capillary growth in the originally developed tumor was also significantly reduced. These results suggest that the clinical setting using TNP-470 may be one of the promising treatments for the metastasis of tumor cells.

Animals↗
PubMed1993

Interindividual variability of carbonyl reductase levels in human livers.

Interindividual variability of carbonyl reductase levels in human livers (N = 11) was examined by measuring reductase activity toward various substrates and by western blot analysis using anti-rat ovarian carbonyl reductase CR2 antibody. The carbonyl reductase activity toward p-nitrobenzaldehyde (PNBA) (58.1 +/- 5.4 nmol/mg protein/min, mean +/- SE) was highest among the substrates examined, followed by 4-benzoylpyridine (4BP) (14.4 +/- 2.0 nmol/mg protein/min) and p-nitroacetophenone (PNAP) (2.00 +/- 0.37 nmol/mg protein/min). The reductase activity (6.33 +/- 0.56 pmol/mg protein/min) toward 13,14-dihydro-15-keto-prostaglandin F2 alpha (15KD-PGF2 alpha), which is a diagnostic substrate for rat ovarian carbonyl reductases, was relatively high compared to that in other species. Western blot analysis revealed that each human liver contained several immunoreactive proteins to anti-CR2 antibody. The activities toward 15KD-PGF2 alpha (r = 0.85, P < 0.01) and 4BP (r = 0.84, P < 0.01), but not PNBA (r = 0.53, not significant) or PNAP (r = 0.52, not significant), were closely correlated with the relative amounts of the high molecular weight immunoreactive proteins determined with a densitometer. Thus, the major carbonyl reductases in human liver are similar to those of rat ovarian enzymes.

Acetophenones↗
PubMed1993

Aromatase activity in human osteoblast-like osteosarcoma cell.

Aromatase activity was studied in cultured human osteosarcoma cell (HOS). HOS was incubated from 12 to 72 hours with 10(-10) M-10(-5) M dexamethasone. Aromatase activity was determined by measuring [3H]H2O released upon the conversion of [1 beta-3H]androstenedione to estrone. HOS showed aromatase activity, and apparent km for [1 beta-3H]androstenedione was 4.46 +/- 0.98 nm (mean +/- SD). The aromatase activity was significantly increased by 10(-9) M-10(-5) M dexamethasone in a dose-dependent manner. Dexamethasone increased Vmax of aromatase activity but did not change its km value. These results suggest that osteoblastic cells have aromatase activity which is regulated by glucocorticoid, and directly convert androgen to estrogen in itself.

Androstenedione↗
PubMed1993

High expression of cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome associated with high secretion of adrenal androgens.

The mechanism of dissociated secretion between adrenal androgens and cortisol observed in several clinical situations remains unclear. We investigated whether the electron transfer systems NADPH-cytochrome P450 reductase and cytochrome b5, both of which had been shown to increase 17,20-lyase activity in vitro, were involved in the reaction selectivity between 17 alpha-hydroxylase and 17,20-lyase in adrenocortical adenomas obtained from eight patients with Cushing's syndrome producing different concentrations of adrenal androgen. In vitro enzyme assay using microsomal fraction of adenoma indicated that all adenomas from seven patients showed almost the same degree of 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activities. However, the 17,20-lyase activities of two adenomas producing high concentrations of adrenal androgens were 3-fold greater than those of other five adenomas producing low concentrations of adrenal androgens. The mRNA concentrations of cytochrome P45017 alpha and 3 beta HSD were approximately the same in all adenomas, whereas those of cytochrome b5 in two adenomas possessing high 17,20-lyase activities were greater than those in other adenomas. The increased levels of cytochrome b5 in the two adenomas were further confirmed at the protein level using Western blot analysis of the microsomal fraction. No significant expression of NADPH-cytochrome P450 reductase was detected in any of the adenomas by Northern blot analysis. These results suggest that the difference in the concentration of cytochrome b5 in adrenal adenomas from patients with Cushing's syndrome may partially account for the difference in the amount of adrenal androgens produced by the tumors.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

A single amino acid substitution (gly743 --> val) in the steroid-binding domain of the human androgen receptor leads to Reifenstein syndrome.

The androgen receptor (AR) from a patient with Reifenstein syndrome (incomplete androgen insensitivity syndrome) was characterized. The patient's pubic skin fibroblasts had normal androgen binding. However, when incubated at 41 C, fibroblasts from the patient had a marked decrease in androgen binding as compared with normal fibroblasts. Analysis of coding sequences of the androgen receptor gene revealed a single nucleotide substitution in exon E, resulting in an amino acid change from glycine (GGG) to valine (GTG) at amino acid 743 within the steroid binding domain of AR. Reconstruction of this mutation by site-directed mutagenesis into a human AR complementary DNA followed by expression in COS1 cells led to production of a mutant AR with no significant difference in androgen binding when cells were incubated with androgen at room temperature. However, in contrast to wild type AR expressed in COS1 cells, the mutant AR had markedly lower androgen-binding affinity at 41 C. The mutant receptor could still stimulate a reporter gene at 37 C but this transcriptional stimulation was also decreased when compared with wild type AR receptor in a chloramphenicol acetyltransferase assay. These results suggest that partial androgen resistance in this patient with Reifenstein syndrome is due to a single point mutation in the steroid binding domain of the androgen receptor.

Adult↗