Neck paraganglioma with a pituitary adenoma. Case report.
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Adenoma↗
Biomedical subjects
K Boekelheide
Publications and source records attributed to K Boekelheide.
The metabolic pathway catalyzed by the tyrosinase of Agaricus bisporus.
N-t-Butyloxycarbonyl-gamma-L-glutaminyl-2-bromo-4-hydroxybenzene alpha-benzyl ester was synthesized as a precursor to gamma-L-glutaminyl-4-hydroxy[2-3H]benzene. With this labeled compound and the previously synthesized gamma-L-glutaminyl-4-hydroxy[3,5-3H]benzene, the stoichiometry of ring substitution was determined for the tyrosinase-catalyzed metabolic pathway of Agaricus bisporus. In this pathway, gamma-L-glutaminyl-4-hydroxybenzene is hydroxylated to gamma-L-glutaminyl-3,4-dihydroxybenzene which is oxidized to gamma-L-glutaminyl-3,4-benzoquinone and a compound of previously unknown structure, "490." The results indicated that the "490" quinone was derived from gamma-L-glutaminyl-3,4-benzoquinone without further ring substitution. A base-catalyzed, nonenzymatic reaction of gamma-L-glutaminyl-3,4-benzoquinone was observed which yielded a compound with a 490 nm chromophore. gamma-Glutamyl transpeptidase cleavage of gamma-L-glutaminyl-3,4-dihydroxybenzene led to the release of 4-aminocatechol which air-oxidized to a compound with identical spectral properties to "490." The structure of "490" was thus determined to be 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one(2-hydroxy-4-iminoquinone). The tyrosinase-catalyzed hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene was found to be optimal at pH 8.0, while the enzymatic oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene was optimal at pH 6.0.
Agaricales↗
Melanocytotoxicity and the mechanism of activation of gamma-L-glutaminyl-4-hydroxybenzene.
gamma-L-Glutaminyl-4-hydroxybenzene is converted by the tyrosinase of the common mushroom, Agaricus bisporus, to the toxic, dormancy-inducing metabolite 2-hydroxy-4-imino-2,5-cyclohexadiene-1-one. Hydroxylation of gamma-L-glutaminyl-4-hydroxybenzene by mammalian tyrosinase was monitored by determining tritium water release from gamma-L-glutaminyl-[3,5-(3)H[4-hydroxybenzene and occurred at only 25% of the rate found with tyrosine. The dihydroxy product of the hydroxylation reaction, gamma-L-glutaminyl-3,4-dihydroxybenzene, was not oxidized by the mammalian enzyme. Therefore, oxidation of gamma-L-glutaminyl-4-hydroxybenzene to sulfhydryl-reactive quinones by mammalian tyrosinase is an unlikely explanation for the hair depigmentation and inhibition of melanocarcinoma growth observed following administration of this compound. Cleavage of gamma-L-glutaminyl-4-hydroxybenzene by gamma-glutamyl transpeptidase releasing p-aminophenol was demonstrated. p-Aminophenol was an active depigmenting and melanocytotoxic compound. N2-Methyl-gamma-L-glutaminyl-4-hydroxybenzene was synthesized, differing from gamma-L-glutaminyl-4-hydroxybenzene only by the presence of a methylated amide linkage. This chemical modification resulted in a compound resistant to cleavage by gamma-glutamyl transpeptidase and lacking in melanocytotoxic activity. gamma-Glutamyl transpeptidase cleavage is proposed as the route for transformation of gamma-L-glutaminyl-4-hydroxybenzene into an active inhibitor of melanocytes.
Aminophenols↗
The role of gamma-glutamyl transpeptidase in the nephrotoxicity of an Agaricus bisporus metabolite.
The mushroom metabolite gamma-L-glutaminyl-3,4-dihydroxybenzene (GDHB) was found to have an LD50 of 100 to 200 mg/kg in neonatal C57Bl/6J mice. Adult mice given 200 mg/kg GDHB showed histopathologic evidence of proximal convoluted tubular injury as early as 2 hours after injection, which progressed by 24 hours to profound acute tubular necrosis. Focal acinar epithelial cell necrosis in the pancreas was also observed. The time course and location of the injury suggested that appearance of the ultimate toxic metabolite could be due to cleavage of GDHB by gamma-glutamyl transpeptidase (GGTP). The reaction in vitro of GDHB with crude porcine GGTP resulted in the release of 4-amino-catechol which air oxidized to 2-hydroxy--4-iminoquinone (HIQ), a known sulfhydryl reagent and cytotoxic compound. Synthesis of N2-methyl-gamma-glutaminyl-3,4-dihydroxybenzene (MeGDHB) provided a compound whose oxidized derivatives, when compared with those of GDHB, had similar half-wave potentials and visible absorption maxima. MeGDHB was resistant to cleavage by GGTP and was without apparent toxicitiy at 2-3 times the LD50 of GDHB. Therefore, cleavage by GGTP, an enzymatic transformation accessible to GDHB but unavailable to MeGDHB, is proposed as the mechanism of activation of the mushroom metabolite. The following pathogenic sequence is indicated: 1) release of 4-aminocatechol from GDHB by the action of GGTP and 2) irreversible injury resulting both from the generation of free radicals by the autoxidation of 4-aminocatechol and from the reaction of HIQ with cellular nucleophils, particularly sulfhydryl groups.
Agaricales↗
Synthesis of gamma-L-glutaminyl-[3,5-3H]4-hydroxybenzene and the study of reactions catalyzed by the tyrosinase of Agaricus bisporus.
gamma-L-Glutaminyl-[3,5-3H]4-hydroxybenzene was synthesized in order to study the kinetics of its hydroxylation by tyrosinase purified from Agaricus bisporus and to explore its role in the induction of the dormant state in the spores of this species. It was found to be unique among the monophenolic substrates for tyrosinase in that the lag period for the hydroxylation reaction decreased with increasing substrate concentration. Unlike previously studied compounds, this phenol appeared to function as an electron donor, allowing it to act as its own co-substrate in the hydroxylation reaction. Its catechol product, gamma-L-glutaminyl-3,4-dihydroxybenzene, was found to be a superior co-substrate, yielding its electrons more readily (oxidation peak potential +0.18 V as compared with +0.65 V for the phenol). In situ periodate oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene to gamma-L-glutaminyl-3,4-benzoquinone confirmed the co-substrate role of the catechol in the hydroxylation reaction. The tyrosinase-mediated oxidation of gamma-L-glutaminyl-3,4-dihydroxybenzene to gamma-L-glutaminyl-3,4-benzoquinone occurred with an apparent Km = 1.54 mM and Vmax = 0.36 mmol/min/mg of enzyme. gamma-L-Glutaminyl-4-hydroxybenzene acted as an inhibitor of the oxidation reaction.
Agaricales↗
Lysozyme catalysis: kinetics of the hydrolysis of cell wall oligosaccharides.
The cleavage of cell wall tetrasaccharide, the beta(1 leads to 4)-linked dimer of the basic repeating disaccharide N-acetyl-D-glucosamine-beta(1 leads to 4)-N-acetyl-D-muramic acid, by lysozyme has been studied at various concentrations of lysozyme and over long time ranges. A theoretical analysis of the kinetic results indicates that direct hydrolysis of the tetrasaccharide by binding in subsities CDEF of the active site of lysozyme is significant at long times relative to the transglycosylation pathway. The binding constant for tetrasaccharide in CDEF is shown to be 10(3) times larger than that determined on the basis of an analysis of kinetic data over a more restricted range of times and concentrations.
Binding Sites↗
Intracellular activation of gamma-L-glutaminyl-4-hydroxybenzene by tyrosinase, a mechanism for selective cytotoxicity against melanocarcinoma.
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Animals↗
The nuclear magnetic resonance determination of the conformation of saccharides bound in subsite D of lysozyme.
The binding of the trisaccharide (2-acetamido-2-deoxy-D-muramic acid)-beta(1 leads to 4)-(2-aceta-mido-2-deoxy-D-glucosyl)-beta(1 leads to 4)-(2-acetamido-2-deoxy-D-muramic acid) to subsites B, C, and D in lysozyme has been studied by 1H nuclear magnetic resonance methods. In particular, the coupling constant between H1 and H2 of the reducing saccharide bound in subsite D has been determined. The coupling constant for the bound saccharide indicates that the dihedral angle between C1 and C2 for the reducing saccharide is not significantly changed upon binding to lysozyme. This result is discussed in terms of other evidence for the role of distortion of the saccharide bound in subsite D in the lysozyme-catalyzed hydrolysis of cell wall oligosaccharides.
Binding Sites↗
Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity.
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Amines↗
Transmembrane versus soluble stem cell factor expression in human testis.
The interaction between stem cell factor (SCF), a ligand produced by Sertoli cells, and its c-kit receptor on germ cells is necessary for successful spermatogenesis in animal models. SCF can be alternatively spliced into soluble and transmembrane forms, and it is the transmembrane form that is required for spermatogenesis in rodents. c-Kit receptors are also present on Leydig cells, and soluble SCF has been implicated in the regulation of testosterone production. This study had two goals: To test the hypothesis that the extent of germ cell production in human males is correlated with the expression of transmembrane SCF, and to examine the relationship between testosterone production and the expression of soluble SCF in humans. Reverse transcriptase polymerase chain reaction was used to determine the ratio of transmembrane-to-soluble SCF in testicular tissue. Clinical analysis, hormonal measurements, and histological methods were used to evaluate the causes of infertility and to seek correlations with the pattern of SCF expression. SCF was preferentially expressed as the transmembrane type in all testicular samples, regardless of the state of germ cell production. Furthermore, the percent of transmembrane SCF expression was independent of clinical and histopathological diagnosis (r(s) = 0.111, n = 28) and unrelated to the extent of spermatogenesis. This contrasts with rat models of testicular injury that exhibit a decreased proportion of transmembrane SCF with atrophy. A significant correlation (r(s) = 0.665, P < .02, n = 16) was found between testosterone levels and percent soluble SCF, which suggests that, in humans, there may be a regulatory interaction between soluble SCF and testosterone.
Biopsy↗
Experimental cryptorchidism protects against long-term 2,5-hexanedione-induced testicular germ cell loss in the rat.
Male infertility is a common side effect of aggressive cancer chemotherapy. One possible approach to decreasing gonadal injury in this setting is the production of artificial cryptorchidism (elevating the testes into the inguinal canal) to produce reversible germ cell loss and cytoprotective hemodynamic changes in the testes. This approach to preserving male germ cell production was explored in a rat model combining experimental cryptorchidism and 2,5-hexanedione intoxication. Rats were protected from irreversible germ cell loss produced by 2,5-hexanedione only when the testes were cryptorchid during the time of intoxication. Sham-operated rats and rats made cryptorchid following intoxication were not protected from 2,5-hexanedione-induced testicular germ cell loss. Decreased delivery of the toxic agent to the cryptorchid testis is the likely explanation of the protective effect.
Animals↗
2,5-hexanedione exposure in the rat results in long-term testicular atrophy despite the presence of residual spermatogonia.
Charles River CD rats (approximate weight, 208 g) were exposed to 1.0% 2,5-hexanedione (2,5-HD) in drinking water for 5 weeks. Rats were killed 27, 60, and 75 weeks after exposure to evaluate the recovery potential following testicular injury. At 27 weeks, normal serum testosterone and significantly elevated serum luteinizing hormone and serum follicle-stimulating hormone levels were found in treated rats. The 2,5-HD-treated rats had low testicular and epididymal weights at all time points (28% and 72% of controls, respectively, at 75 weeks). Microscopically, there was a generalized loss of postspermatogonial germ cells at all time points, with no seminiferous tubules exhibiting normal spermatogenesis at 75 weeks. However, a relatively constant population of 3.1 to 3.7 spermatogonia/100 Sertoli cells was found in atrophic seminiferous tubules at all time points. The presence of a constant residual population of type A spermatogonia without a normal mass of more mature germ cells and the observed hormonal alterations suggest that 2,5-HD intoxication produced a lengthy disruption in local testicular homeostatic mechanisms that control spermatogenesis.
Animals↗
In vitro and in vivo studies of the molecular pathogenesis of n-Hexane neuropathy.
In vivo intoxication of rats with 2,5-hexanedione and 3,4-dimethyl-2,5-hexanedione, which results in axonal swellings filled with neurofilaments, has been combined with in vitro exposure of proteins and model amines to the gamma-diketones in attempts to explain the molecular pathogenesis of n-hexane neuropathy and related neurofilament neuropathies. The heretofore untested gamma-diketone, 3,4-dimethyl-2,5-hexanedione is proposed as a "missing link" between beta, beta'-iminodipropionitrile, which produces proximal aggregates of neurofilaments, and 2,5-hexanedione, acrylamide, and carbon disulfide, which result in neurofilament-filled swellings in the distal axon.
Animals↗
Development and characterization of a prepubertal rat Sertoli cell line, 93RS2.
Sertoli cells in the seminiferous epithelium provide both structural and nutritional support to germ cells during spermatogenesis. Primary Sertoli cells in culture are an effective tool for the in vitro study of Sertoli cell function; however, primary cultures are inherently variable, time consuming to prepare, expensive, and wasteful of animals. We therefore developed a Sertoli cell line, called 93RS2, by immortalizing primary Sertoli cells derived from prepubertal rats with SV40 tsA255. This cell line proliferates at the permissive temperature (32 degrees C) and has enhanced expression of a differentiated Sertoli cell phenotype at the nonpermissive temperature (40-41 degrees C). Cytogenetic analysis demonstrated that 93RS2 has 42 chromosomes per cell, the same as a normal rat. mRNA analysis showed that this cell line, when cultured at a nonpermissive temperature, exhibited increased expression of transferrin in the presence of testosterone and enhanced expression of sulfated glycoprotein-2. A tumorigenicity assay showed that 93RS2 cells were temperature-dependent for growth in soft agar and were capable of forming tumors in nude mice. In conclusion, this rat 93RS2 cell line should be useful for the study of Sertoli cell function.
Animals↗