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31.
C S Aaron L F Stankowski P R Harbach R Valencia J K Mayo J Mirsalis J H Mazurek K L Steinmetz S K Wiser D M Zimmer 《Mutation research》1989,223(2):111-120
U-48753E is a potential human drug which was subjected to a battery of short-term assays for genetic activity. The compound was negative in the Salmonella (Ames) test, the in vitro UDS assay, the mouse bone-marrow micronucleus test and the Drosophila sex-linked recessive lethal assay. However, it was weakly positive in the CHO/HPRT assay in the presence of metabolic activation (S9). The weak positive response might easily have been labeled artifactual since there was no dose response and the dose level producing positive findings varied from experiment to experiment. In addition, the weak positive response was not confirmed in V79 cells. However, a reproducible dose-related increase in mutants was observed in the AS52/XPRT assay in the presence of S9. Metabolism of this drug proceeds through conversion of aliphatic N-methyl groups to formaldehyde. Addition of formaldehyde dehydrogenase to the S9 resulted in elimination of the mutagenicity of the compound in AS52 cells. Thus, the mutants were probably induced by formaldehyde. From the endogenous levels of formaldehyde in human blood, and the limiting potential therapeutic dose levels, the genotoxic hazard associated with U-48753E is marginal. This assessment of risk and its quantitation depend upon an understanding metabolism and exposure limits imposed by known side effects of the drug. This study can serve as a model for quantitative genetic risk assessment when mutagenicity is due to N-demethylation and formation of formaldehyde in situ. 相似文献
32.
The in vitro unscheduled DNA synthesis assay (UDS) is part of the routine genetic toxicology screening at The Upjohn Company. The purpose of this paper is to report results for 8 compounds which were tested in the in-house genetic toxicology program. These compounds represent diverse chemical structure and most of them entered the screening program because they are biologically active in efficacy screens. All tests were carried out under Good Laboratory Practices Regulations of the U.S. Food and Drug Administration. None of the materials reported here produced an increase in UDS and therefore the UDS results with these compounds do not suggest potential for genotoxicity. 相似文献
33.
Dr. Stefan B. Cajander M. P. Hugin Peter Kristensen Aaron J. W. Hsueh 《Cell and tissue research》1989,257(1):1-8
Summary The observation that tissue-type plasminogen activator (tPA) activity increased dramatically in preovulatory follicles has led to the hypothesis that plasminogen activation is causally related to follicle rupture. With immunohistochemistry, we have studied the appearance of tPA in ovaries of immature rats induced to ovulate and in adult cycling rats. Treatment of immature female rats with a single dose of pregnant mare serum gonadotropin (PMSG) induced follicular maturation. A subsequent human chorionic gonadotropin (hCG) injection resulted in follicle rupture 12–14 h later. PMSG treatment alone did not induce appearance of tPA-immunoreactive cells in any ovarian compartment. After hCG stimulation, however, theca cells, granulosa cells, and oocytes of pre- and postovulatory follicles displayed distinct tPA immunoreactivity. Fibroblastlike cells in the theca layers and tunica albuginea of the follicle apex also demonstrated localized cytoplasmic tPA reactivity. In addition to tPA synthesis in preovulatory follicles, hCG also induced tPA staining in the theca (but not granulosa) layers of non-ovulatory follicles. At 24 h after hCG treatment, there was a marked tPA staining in developing corpora lutea, ovulated ova, and oviductal epithelium. Ovaries from regularly cycling adult rats displayed a similar ovulation-related pattern of tPA immunostaining. The appearance of tPA in different cell types of the preovulatory follicle and in the fibroblast-like cells at the follicle apex, strengthens the hypothesis of a direct involvement of tPA in follicle rupture. Presence of tPA in postovulatory oocytes, cumulus cells, and surrounding oviductal epithelium may also indicate a role for tPA in the transfer of eggs in the oviduct.This work was supported by NIH Research Grants HD-14084; 12303 相似文献
34.
Production of monocyte chemotactic and activating factor (MCAF) by human dermal fibroblasts in response to interleukin 1 or tumor necrosis factor 总被引:16,自引:0,他引:16
C G Larsen C O Zachariae J J Oppenheim K Matsushima 《Biochemical and biophysical research communications》1989,160(3):1403-1408
Normal human dermal fibroblasts rapidly expressed (less than 30 min.) considerable mRNA for monocyte chemotactic and activating factor (MCAF) and released high levels of biological activity in response to interleukin 1 (IL 1) or tumor necrosis factor (TNF). In contrast, cultured normal human keratinocytes did not express MCAF mRNA when stimulated with IL 1 or TNF. These results suggest the important role of dermal fibroblasts, the predominant cells in dermal connective tissue, in the recruitment of monocytes during inflammation. This is the first report of the induction of MCAF by IL 1 or TNF in any cell type. 相似文献
35.
Cloning and sequencing of the cDNA for human monocyte chemotactic and activating factor (MCAF) 总被引:28,自引:0,他引:28
Y Furutani H Nomura M Notake Y Oyamada T Fukui M Yamada C G Larsen J J Oppenheim K Matsushima 《Biochemical and biophysical research communications》1989,159(1):249-255
cDNA clones having a nucleotide sequence encoding a human monocyte chemotactic and activating factor (MCAF) were isolated and sequenced. The amino acid sequence deduced from the nucleotide sequence reveals the primary structure of the MCAF precursor to be composed of a putative signal peptide sequence of 23 amino acid residues and a mature MCAF sequence of 76 amino acid residues. The amino acid sequence of MCAF showed 25-55% homology with other members of an inducible cytokine family, including macrophage inflammatory protein and some putative polypeptide mediators known as JE, LD78, RANTES and TCA-3. This suggests that MCAF is a member of family of factors involved in immune and inflammatory responses. 相似文献
36.
Carboxypeptidase A: mechanism of zinc inhibition 总被引:1,自引:0,他引:1
Zinc ions competitively inhibit carboxypeptidase A from bovine pancreas. The state(s) of hydroxylation of zinc and their possible site(s) of interaction with the enzyme have been investigated by determining the strength of zinc inhibition over pH range 4.6-10.5. The inhibition kinetics were recorded under stopped-flow conditions using the alpha-Val isozyme and the peptide substrate Dns-Gly-Ala-Phe in 0.5 M NaCl at 25 degrees C. The pH dependence of pKI follows a pattern which indicates that the enzyme is selectively inhibited by zinc monohydroxide, ZnOH+ (KI = 7.1 X 10(-7) M). The formation of the inhibitory ZnOH+ complex from fully hydrated Zn2+ is characterized by an ionization constant of 9.05, and the consecutive conversion of ZnOH+ to Zn(OH)2, Zn(OH)3-, and Zn(OH)4(2-) complexes takes place with ionization constants of 9.75, 10.1, and 10.5, respectively. Ionization of a ligand, LH, in the enzyme's inhibitory site (pKLH 5.8) is obligatory for binding of the ZnOH+ complex. The enzymatic activity (kcat/Km) is influenced by three ionizable groups: pKEH2 5.78, pKEH 8.60, and pKE 10.2. Since the values of pKLH and pKEH2 are virtually identical, it is possible that the inhibitory ZnOH+ complex interacts with the group responsible for pKEH2. Previous studies have suggested that pKEH2 reflects the ionization of Glu-270 and its interaction with a water molecule coordinated to the catalytic zinc ion. It is proposed that the inhibitory zinc ion binds to the carboxylate of Glu-270 and that the inhibition process is specific for zinc monohydroxide because it allows the formation of a stabilizing hydroxide bridge between the inhibitory and catalytic zinc ions. 相似文献
37.
M Hirasawa K A Gray M R Ondrias R W Larsen R W Shaw K J Morrow D B Knaff 《Biochimica et biophysica acta》1989,994(3):229-234
A recently discovered form of spinach catalase that contains both a novel heme and protoheme as prosthetic groups has been characterized using immunological and spectroscopic techniques. The enzyme appears to be a dimer of identical Mr 60,000 monomers. Extraction of the non-covalently bound prosthetic groups, followed by thin-layer chromatography of the extract, suggested that the novel heme contains four carboxylic acid side-chain groups. The resonance Raman spectrum of the resting enzyme indicates that the protoheme prosthetic group is five-coordinate and high-spin. The enzyme was shown to bind formate, azide and cyanide. Cyanide and azide binding to catalase are biphasic, suggesting the existence of two different binding sites for cyanide and azide in the enzyme. Results obtained from EPR and resonance Raman spectroscopies also support the hypothesis that two different ligand-binding sites are present in the enzyme. Western blots suggest that the Mr 60,000 peptide of the novel heme-containing catalase is similar or identical to that of a previously characterized, exclusively protoheme-containing, tetrameric catalase. 相似文献
38.
Synopsis New information regarding the ecology ofScytalina cerdale was obtained over a four year period as a consequence of a long-term marine ecological study at the Diablo Canyon Power Plant (DCPP), San Luis Obispo County, California. Twenty intertidal fish surveys were conducted at approximately quarterly intervals, between March 1979 and June 1983, at three separate rocky shore locations (stations). During each survey, a total of 108 square meters (36 m2 per station) was searched for fish during periods of low tide. A total of 280S. cerdale were collected, identified, measured, and released back into the same 4 m2 area, from the same intertidal station (Diablo Cove), throughout the study period. This limited intertidal occurrence most likely reflectsS. cerdale microhabitat requirements; a combination of intertidal elevation (mean = +0.3 MLLW), substratum specificity (loose gravel, 5–10mm size range, overlying a base of sand and shell fragments), and degree of wave exposure (semi-protected). Throughout the study,S. cerdale was seasonally more abundant during summer months (June through August) and less abundant during winter months (November through February). The only exception to this abundance trend followed the 1982 winter storms, which coincided with an El Niño event, whenS. cerdale abundance uncharacteristically dropped during the subsequent 1983 spring and summer surveys. Mean total lengths did not vary greatly, reflecting the absence of early juvenile fishes, and relatively high mean fish densities (3.5 fish per m2 for 20 surveys) were recorded. Qualitative comparisons betweenS. cerdale abundance and seasonal changes in water temperature indicated an inverse relationship. Gravid females, demersal egg masses, and early juvenile individuals were never observed during the four years of the study. This suggests that unlike most other intertidal fishes, particularly other blennioids,S. cerdale may not utilize the intertidal zone for reproductive and recruitment purposes; Diablo Canyon is the most southerly reported distribution for this intertidal species, and therefore, may not entirely represent the species' biology as a whole. 相似文献
39.
Dorthe Arenholt-Bindslev Børge Larsen Mohamed Abdulla Arne Jepsen 《Biological trace element research》1988,15(1):257-266
In cultures of rat tongue epithelial cells, cell proliferation following incubation with different doses of the potent tumor promoter TPA has been studied by using a stathmokinetic method counting colchicine arrested metaphases. It was demonstrated that 24 h incubation with concentrations higher than 5 ng TPA/mL medium caused inhibition, whereas below 5 ng TPA/mL medium caused stimulation of the mitotic activity reaching a maximum around 30 h from the start of the incubation period. Based on the evidence of the anticarcinogenic effect of selenium in several animal models, experiments have been performed elucidating the influence of an atoxic dose (1/1.000.000M) of selenite on the observed TPA-induced cell proliferation. Our results indicate that addition to the culture medium of an atoxic dose of selenite, not affecting the mitotic activity of control cultures, inhibits the TPA-induced stimulation of cell proliferation. 相似文献
40.
Acardiac fetus in a triplet pregnancy 总被引:1,自引:0,他引:1
The acardiac monster represents one of the most severe but rare congenital anomalies. It occurs only in multiple gestations associated with vascular anastomoses between the affected fetus and its co-twin. The prenatal diagnosis of an acardiac fetus must be suspected in any multiple gestation in which cardiac activity cannot be documented sonographically in a growing fetus. We report an acardiac fetus occurring in a spontaneously conceived triplet pregnancy. A review of the literature, including pathogenetic theories and sonographic reports, is discussed. 相似文献