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51.
Carcinogen metabolism in human skin grafted onto athymic nude mice: a model system for the study of human skin carcinogenesis 总被引:1,自引:0,他引:1
M Das P Asokan P S Don G G Krueger D R Bickers H Mukhtar 《Biochemical and biophysical research communications》1986,138(1):33-39
Human skin grafted onto athymic nude mice maintains its major histological features and may provide a useful system with which to assess the carcinogen interaction with human skin. Significant differences were observed in basal levels of cytochrome P-450 and cytochrome P-448-dependent monooxygenase activities between human grafted and nude mouse epidermis. Topical application of crude coal tar (CCT) to human skin transplanted onto nude mice resulted in 3.9 & 3.5; 3.2 & 2.9 and 1.1 & 1.2 fold increases in mouse and human epidermal aryl hydrocarbon hydroxylase (AHH), ethoxyresorufin deethylase (ERD) and ethoxycoumarin deethylase (ECD) activities, respectively. CCT applied topically to mouse skin resulted in 27.8 & 6.4; 12.8 & 3.3 and 1.7 & 2.6 fold increases in mouse and human epidermal AHH, ERD and ECD activities, respectively. Topical application of coal tar either onto human transplanted skin or to mouse skin also resulted in substantial induction of hepatic and pulmonary AHH and ERD activities. These studies indicate that human skin grafted onto nude mice preserves its metabolic capacity and offers a useful model system with which to assess the effects of polycyclic aromatic hydrocarbons and CCT on cutaneous xenobiotic metabolism in the human population. 相似文献
52.
DR. Myron A. Mehlman DR. Emil A. Pfitzer DR. Robert A. Scala The Committee to Promote Principles of Reduction Refinement Replacement of Animal Testing in Industrial Toxicology Laboratories 《Cell biology and toxicology》1989,5(3):349-358
The Committee to Promote Principles of Reduction, Refinement and Replacement of Animal Testing in Industrial Toxicology Laboratories was established in 1987 to work toward industrywide improvements in laboratory animal testing methods. The committee's goals are to gather information about effective nonanimal testing techniques and other methods of conserving and improving the care of laboratory animals, to work toward the systematic validation of nonanimal alternatives, and to disseminate useful information about progressive programs and policies throughout the industrial toxicology community. This is the first in a continuing series of reports the committee plans to produce as part of an ongoing program to promote communication among industrial toxicologists about successful methods of reducing, refining and replacing animal testing. Here are some of the report's major findings: (1) Animal care and use committees charged with the oversight of laboratory animal use are a universal practice at the companies surveyed. (2) Significant reductions in the number of animals used for acute toxicity testing have taken place at all the companies during the last 5- to 10-year period. (3) Structure-activity relationships (predicting a test compound's properties based on the known properties of familiar chemicals with similar structures) are widely used to minimize, but not replace, the use of animals. (4) Tissue and organ culture systems are being used with increasing frequency for screening and mechanistic studies, but are not completely replacing animal evaluations as a final step. (5) There is a pressing need for the systematic and scientifically sound validation of nonanimal alternative techniques to reduce the use of animals in toxicology testing while satisfying requirements for the protection of public safety. 相似文献
53.
Hamid Reza Rezvani Walid Mahfouf Nsrein Ali Cecile Chemin Cecile Ged Arianna L. Kim Hubert de Verneuil Alain Ta?eb David R. Bickers Frédéric Mazurier 《Nucleic acids research》2010,38(3):797-809
The regulation of DNA repair enzymes is crucial for cancer prevention, initiation, and therapy. We have studied the effect of ultraviolet B (UVB) radiation on the expression of the two nucleotide excision repair factors (XPC and XPD) in human keratinocytes. We show that hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of XPC and XPD. Early UVB-induced downregulation of HIF-1α increased XPC mRNA expression due to competition between HIF-1α and Sp1 for their overlapping binding sites. Late UVB-induced enhanced phosphorylation of HIF-1α protein upregulated XPC mRNA expression by direct binding to a separate hypoxia response element (HRE) in the XPC promoter region. HIF-1α also regulated XPD expression by binding to a region of seven overlapping HREs in its promoter. Quantitative chromatin immunoprecipitation assays further revealed putative HREs in the genes encoding other DNA repair proteins (XPB, XPG, CSA and CSB), suggesting that HIF-1α is a key regulator of the DNA repair machinery. Analysis of the repair kinetics of 6-4 photoproducts and cyclobutane pyrimidine dimers also revealed that HIF-1α downregulation led to an increased rate of immediate removal of both photolesions but attenuated their late removal following UVB irradiation, indicating the functional effects of HIF-1α in the repair of UVB-induced DNA damage. 相似文献
54.
Purified chloroplast tRNAs were isolated fromPisum sativum leaves and radioactively labeled at their 3′ end using tRNA nucleotidyl transferase and α32P-labeled CTP. Pea ctDNA was fragmented using a number of restriction endonucleases and hybridized with thein vitro labeled chloroplast tRNAs by DNA transfer method. Genes for tRNAs have been found to be dispersed throughout the chloroplast
genome. A closer analysis of the several hybrid regions using recombinant DNA plasmids have shown that tRNA genes are localized
in the chloroplast genome in both single and multiple arrangements. Two dimensional gel electrophoresis of total ct tRNA have
identified 36 spots. All of them have been found to hybridize withPisum sativum ctDNA. Using recombinant clones, 30 of the tRNA spots have been mapped inPisum sativum ctDNA. 相似文献
55.
H Mukhtar M Athar D R Bickers 《Biochemical and biophysical research communications》1987,145(2):749-753
The incubation of microsomes of whole skin, dermis and epidermis with 14C testosterone in the presence of NADPH resulted in the formation of 6 beta-, 7 alpha- and 16 alpha-testosterone. Maximum enzyme activity occurred in epidermal microsomes followed by dermis and whole skin. Epidermal testosterone hydroxylase activity required NADPH and oxygen and was found to be inhibited by SKF 525A and metyrapone. Our data strongly suggest that testosterone is metabolized by the cytochrome P-450 dependent monooxygenase in skin and provides the first evidence for an endogenous substrate for cytochrome P-450 in this tissue. The formation of several hydroxylated products further suggests the existence of multiple isozymes of cytochrome P-450 in rat skin. These studies provide additional evidence that target tissues may modulate their hormone levels by enzyme pathways that are locally regulated. 相似文献
56.
Mutations which improve the efficiency of recombination should affect
either the proteins which mediate recombination or their substrate, DNA
itself. The former mutations would be localized to a few sites. The latter
would be dispersed. Studies of hybridization between RNA molecules have
suggested that recombination may be initiated by a homology search
involving the "kissing" of the tips of stem loops. This predicts that, in
the absence of other constraints, mutations which assist the formation of
stem loops would be favored. From comparisons of the folding of normal and
shuffled DNA sequences, I present evidence for an evolutionary selection
pressure to distribute stem loops generally throughout genomes. I propose
that this early pressure came into conflict with later local pressures to
impose information concerning specific function. The conflict was
accommodated by permitting sections of DNA concerned with a specific
function to evolve in dispersed segments. Traces of the conflict seem to be
present in some modern intron-containing genes. Thus, introns may have
allowed the interspersing of selectively advantageous stem loops in coding
regions of DNA.
相似文献
57.
David R. Bickers Rakesh Dixit Hasan Mukhtar 《Biochemical and biophysical research communications》1982,108(3):1032-1039
Epidermal microsomal cytochrome P-450 was rapidly degraded when microsomes were aerobically exposed to ultraviolet light in the presence of hematoporphyrin derivative (HPD). Destruction of microsomal cytochrome P-450 was accompanied by loss of heme content, and inhibition of catalytic activity of the monooxygenases, including aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase. Destruction of cytochrome P-450 by photosensitized HPD was oxygen dependent. Quenchers of singlet oxygen, including 2,5 dimethylfuran, histidine, and B-carotene, largely pre- vented photodestruction of cytochrome P-450. Inhibitors of hydroxyl radical including benzoate and mannitol, protected microsomal cytochrome P-450 from destruction. Superoxide dismutase and catalase, scavengers of superoxide anion and hydrogen peroxide, respectively, had no protective effect. These results indicate that generation of singlet oxygen and hydroxyl radicals during hematoporphyrin photosensitization is associated with rapid degradation of cytochrome P-450 and heme in epidermal microsomes, and suggest a novel target for this type of tissue damage in the skin. 相似文献
58.
A requirement for trypsin-sensitive cell-surface components for cell-cell interactions of embryonic neural retina cells 总被引:5,自引:3,他引:2
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A quantitative assay was used to measure the rate of collection of a population of embryonic neural retina cells to the surface of cell aggregates. The rate of collection of freshly trysinized cells was limited in the initial stages by the rate of replacement of trypsin-sensitive cell- surface components. When cells were preincubated, or "recovered," and then added to cell aggregates, collection occurred at a linear rate and was independent of protein and glycoprotein synthesis. The adhesion of recovered cells was temperature and energy dependent, and was reversibly inhibited by cytochalasin B. Colchicine had little effect on collection of recovered cells. Antiserum directed against recovered cell membranes was shown to bind to recovered cells by indirect immunofluorescence. The antiserum also was shown to inhibit collection of recovered cells to aggregates, suggesting that at least some of the antigens identified might be involved in the adhesion process. The inhibitory effect of the antiserum was dose dependent . Freshly trypsinized cells absorbed neither the immunofluorescence activity nor the adhesion-inhibiting activity. Recovered cells absorbed away both activities. In specificity studies, dorsal neural retina cells adhered to aggregates of ventral optic tectum in preference to aggregates of dorsal optic tectum. The adhesive specificity of the dorsal retina cells was less sensitive to trypsin than the adhesive specificity of ventral retina cells which adhered preferentially to dorsal tectal aggregates only after a period of recovery. 相似文献
59.
Induction of drug-metabolizing enzymes and aryl hydrocarbon hydroxylase by microscope immersion oil 总被引:1,自引:0,他引:1
Microscope immersion oil when administered intraperitoneally or applied to skin in experimental animals substantially increased liver weight, microsomal protein, NADPH-cytochrome c reductase activity, cytochrome P-450 content and the metabolism of the model substrates, ethylmorphine and benzo(a)pyrene. Immersion oil caused the induction of the polycyclic hydrocarbon type of hemoprotein, cytochrome P-448. When applied to skin, the oil also caused an 11-fold increase in benzo(a)pyrene hydroxylase activity at the skin sites. 相似文献
60.