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181.
The lymphocyte Hprt gene has been used extensively as a reporter locus to
monitor the mutational effects of the exposure of animals to genotoxicants.
Implicit in this view of the function of a reporter gene is the assumption
that its mutagenic response is representative of that of other genes in the
organism. As a test of this hypothesis we compared the frequency of
6-thioguanine-resistant (TGr) mutants at the Hprt locus with the mutant
frequency (MF) induced at another locus, the ouabain resistance (Oua)
locus. The frequency of spontaneous OUA(R) mutants was estimated to be
1.1x10(-7) (MF between <0.3 and 1.1x10(- 7)), which was approximately
30-fold less than the spontaneous TGr MF. Following treatment with
N-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two dose
levels (50 and 150 mg/kg ENU) and two time points (3 and 6 weeks
post-exposure) was consistently 8- to 9-fold lower than the corresponding
TGr MF. Thus the mutagenic response of the Oua locus closely paralleled
that of the Hprt locus, indicating a similarity in their response to ENU.
In addition, the Oua locus was 3-4 times more sensitive than the Hprt locus
to the mutagenic effect of ENU, as measured by the fold increase in MF over
the background level. The number of ENU-mutable sites capable of resulting
in a TGr or OUA(R) phenotype, otherwise known as the mutation target size,
was estimated to differ by an order of magnitude between the two loci. This
difference in target size correlates with, and therefore may largely
account for, the difference in induced MF between both loci.
相似文献
182.
Glauce SB Viana Carolina C Ana Medeiros Michelle R Ana Lacerda Kalyne AM L Leal Tiago G Vale F José deAbreu Matos 《BMC pharmacology》2004,4(1):1-7
Background
Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.Results
DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.Conclusion
Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients. 相似文献183.
184.
柳珊瑚酸对离体豚鼠气管的兴奋作用 总被引:2,自引:0,他引:2
柳珊瑚酸(suberogorgin,Sub)依浓度提高离体豚鼠气管张力,其ED50为52.5μmol·L-1,比Gal和ACh弱。Sub对气管张力作用的剂量—效应曲线可因Atr0.13μmol·L-1,CBT2.4μg·mL-1或TTX1μmol·L-1而右移或下移,最大效应降低。Atr0.65μmol·L-1完全拮抗Sub的作用。在Gal35.5μmol·L-1致挛的气管ACh使气管张力进一步提高而Sub不改变气管张力。 相似文献
185.
Aneuploidy and percentage of S-phase cells determined by flow cytometry correlate with cell phenotype in childhood acute leukemia 总被引:6,自引:1,他引:5
Look AT; Melvin SL; Williams DL; Brodeur GM; Dahl GV; Kalwinsky DK; Murphy SB; Mauer AM 《Blood》1982,60(4):959-967
Cellular DNA content distributions of propidium-iodide-stained bone marrow blasts were determined by flow cytometry (FCM) for 225 untreated children with acute leukemia and were correlated with leukemia cell phenotype and karyotype. Aneuploidy of the primary malignant stem line was detected in 54 cases (24%): 51 hyperdiploid and 3 hypodiploid. A second stem line with approximately twice the DNA content of the primary stem line was recognized by FCM in 28 cases (23 ALL, 5 ANLL) and may be an important source of leukemia cell heterogeneity. The degree of DNA content abnormality detected by FCM was highly correlated (r = 0.98) with the number of whole chromosome gains or losses in the leukemia karyotype. Aneuploidy detectable by FCM was more frequent in acute lymphoblastic leukemia (ALL) (52 of 173, 30.1%) than in acute nonlymphoblastic leukemia (2 of 52, 3.8%) (p less than 0.001). In the ALL group, aneuploidy was significantly correlated with the cell surface expression of common ALL antigen: 46 of 127 antigen-positive cases were aneuploid compared to 6 of 46 antigen-negative cases (p less than 0.003). Only 2 of 21 cases of T-cell ALL without common ALL antigen had detectable aneuploidy, which was significantly less than in the common ALL group (p = 0.02). The median percentage of cells in S- phase was significantly greater for B-cell and erythrocyte rosette- positive T-cell ALL, than for the other phenotypic subgroups. We conclude that aneuploidy and S-phase cell percentage are correlated with the state of leukemia cell differentiation. The biologic basis for the correlation is not established, but may be linked to the process of malignant transformation. 相似文献
186.
In the presence of suboptimal inducing amounts of dimethylsulfoxide or hexamethylenebisacetamide, a major proportion of uncommitted murine erythroleukemia (MEL) cells was found to be precommitted or primed for commitment, which was demonstrated by their rapid commitment to terminal differentiation when recultured for short periods of time (three to six hours) with fresh inducer. These same cells did not commit if left in the original inducer-containing media or if replated in fresh media without inducer. The two inducers could be interchanged in the priming and postpriming period without affecting the commitment event. However, hemin, an agent that induces hemoglobin synthesis without commitment, showed no ability to enhance commitment of a primed cell population. The rapid commitment of primed cells was inhibited by 12-O-tetradecanoylphorbol-13-acetate and cordycepin but not by cycloheximide. The latter finding indicated that this rapid inducer- dependent commitment event required new RNA synthesis but not new protein synthesis. The precommitment state was lost within six hours of the growth of cells in the absence of inducer but could be sustained longer if cells were incubated in cycloheximide. These studies characterize a precommitment state not previously described and one that appears during chemically induced differentiation in the absence of metabolic inhibitors. The stabilization of these precommitted cells by cycloheximide suggests that the reversibility of precommitment involves new protein synthesis. These findings show that MEL cells proceed to terminal differentiation by accumulating unstable products that must be maintained by the inducer until the final commitment event. 相似文献
187.
188.
189.
抗三尖杉酯碱HL-60细胞的抗程序性细胞死亡及其克服 总被引:13,自引:0,他引:13
三尖杉酯碱(harringtonin,HT)是中国产植物海南粗榧(CephalotaxushainanensisLi)中提取的一种抗肿瘤药物,对急性粒细胞白血病、急性单核细胞白血病有较好疗效(1)。三尖杉酯碱可非常有效地诱导敏感HL-60细胞程序性死亡(apoptosis,Apo)(2,3)。但超过半致死剂量(IC50)近百倍的HT却不能诱导抗三尖杉酯碱细胞HT12程序性死亡。如用维拉帕米(verapamil,Vp)10μg·ml-1逆转多药抗性后,HT虽可诱导HT12细胞程序性死亡,但与敏感细胞相比,出现程序性细胞死亡的时间大大推迟,用药浓度也提高约10倍。这些结果提示:程序性细胞死亡可能作为肿瘤细胞是否已形成抗药性的标志之一,同时也说明程序性细胞死亡相关因子可能参与肿瘤细胞抗药性的形成。 相似文献
190.