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981.
The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic -cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.Abbreviations CPH
cyproheptadine
- CPH-epoxide
cyproheptadine-10-11-epoxide
- DMCPH
desmethylcyproheptadine
- DMCPH-epoxide
desmethylcyproheptadine-10,11-epoxide
- HPLC
high-performance liquid chromatography
- KBB
Krebs biocarbonate buffer
Recipient of a Society of Toxicology Predoctoral Research Fellowship.Present address: Department of Biochemistry, The University of Hong Kong, Hong Kong. 相似文献
982.
Study of the in vitro bioactivation of albendazole in human liver microsomes and hepatoma cell lines
Sylvie Rolin Hajar Souhaili-El Amri Anne-Marie Batt Michele Levy Denyse Bagrel Gerard Siest 《Cell biology and toxicology》1989,5(1):1-14
The metabolism of albendazole (ABZ), a benzimidazole anthelminthic, was studied in either microsomal preparations of human liver biopsies or cultured human hepatoma cell lines. Metabolites were analyzed by HPLC. Our data show that microsomes from human biopsies and two human cell lines, HepG2 and Hep3B, oxidize the drug to the sulfoxide very efficiently, whereas the third cell line tested, SK-HEP-1, does not. Both cytochrome P-450 dependent monooxygenases and favin-containing monooxygenases appear to be involved in human ABZ metabolism. Using the cell line displaying the highest ABZ-metabolizing activity, HepG2, the cytotoxic and the inducing effects of the parent drug ABZ and of two primary metabolites, the sulfoxide and the sulfone were studied. These three chemicals provoked a rise in mitotic index resulting from cell division blockage at the prophase or at the metaphase (ABZ metabolites) stage, and ABZ was more cytotoxic than its metabolites. With regard to enzyme-inducing effects, our data clearly demonstrate that the sulfoxide and, to a lesser degree, the sulfone are potent inducers of some drug metabolizing enzymes (i.e., cytochrome P-488 dependent monooxygenases and UDP glucuronyltransferase), whereas ABZ fails to increase and even slightly decreases these enzymatic activities. In conclusion, the HepG2 human hepatoma cell line appears to be suitable for the study of many parameters of metabolism and action of ABZ and other structurally related compounds in humans.Abbreviations ABZ
albendazole
- B[a]P
benzo[a]pyrene
- HPLC
high-performance liquid chromatography
- MC
3-methylcholanthrene
- MFO
mixed-function oxidase
- UDPGT
UDP-glucuronyltransferase 相似文献
983.
C. A. Schreiner D. A. Edwards R. H. McKee M. Swanson Z. A. Wong S. Schmitt P. Beatty 《Cell biology and toxicology》1989,5(2):169-188
Catalytic reforming is a refining process that converts naphthenes to aromatics by dehydrogenation to make higher octane gasoline blending components. A portion of this wide boiling range hydrocarbon stream can be separated by distillation and used for other purposes. One such application is a mixture of predominantly 9-carbon aromatic molecules (C9 aromatics, primarily isomers of ethyltoluene and trimethylbenzene), which is removed and used as a solvent — high-flash aromatic naphtha. A program was initiated to assess the toxicological properties of high-flash aromatic naphtha since there may be human exposure through inhalation or external body contact. The current study was conducted partly to assess the potential for mutagenic activity and also to assist in an assessment of carcinogenic potential. The specific tests utilized included the Salmonella/mammalian microsome mutagenicity assay, the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) forward mutation assay in CHO cells, in vitro chromosome aberration and sister chromatid exchange (SCE) assays in CHO cells, and an in vivo chromosome aberration assay in rat bone marrow.There was no evidence that high-flash aromatic naphtha was either a gene or chromosomal mutagen. Thus it is unlikely to be a genotoxic carcinogen.Abbreviations Brdu
5-Bromo-2-deoxyuridine
- C9
Aromatic species with 9 carbons (i.e., ethyl toluene and trimethyl benzene isomers)
- CE
Cloning efficiency
- CHO
Chinese hamster embryo
- CP
Cyclophosphamide
- DMSO
Dimethyl sulfoxide
- HGPRT
Hypoxanthine-guanine phosphoribosyl transferase
- HVAC
Heating, Ventilation, Air Conditioning
- 3MC
3 Methylcholanthrene
- MMC
Mitomycin C
- MMS
Methyl methanesulfonate
- S9
S9 Mammalian microsomal enzyme activation mixture
- SCE
Sister chromatid exchange 相似文献
984.
Refinement of distance geometry (DG) structures of EETI-II (Heitz et al.: Biochemistry 28:2392-2398, 1989), a member of the squash family trypsin inhibitor, have been carried out by restrained molecular dynamics (RMD) in water. The resulting models show better side chain apolar/polar surface ratio and estimated solvation free energy than structures refined "in vacuo." The consistent lower values of residual NMR constraint violations, apolar/polar surface ratio, and solvation free energy for one of these refined structures allowed prediction of the 3D folding and disulfide connectivity of EETI-II. Except for the few first residues for which no NMR constraints were available, this computer model fully agreed with X-ray structures of CMTI-I (Bode et al.: FEBS Lett. 242:285-292, 1989) and EETI-II complexed with trypsin that appeared after the RMD simulation was completed. Restrained molecular dynamics in water is thus proved to be highly valuable for refinement of DG structures. Also, the successful use of apolar/polar surface ratio and of solvation free energy reinforce the analysis of Novotny et al. (Proteins 4:19-30, 1988) and shows that these criteria are useful indicators of correct versus misfolded models. 相似文献
985.
The enantioseparation of the sherry aroma components 5-oxo-4-hydroxyhexanoic acid γ-lactone (solerone) and 4,5-dihydroxyhexanoic acid γ-lactone (solerole) is achieved, using Chiraspher (Merck) as the chiral HPLC phase and the optical purity ascertained directly by HRGC with heptakis(3-O-acetyl-2,6-di-O-pentyl)-β-cyclodextrin (Lipodex D) as the chiral stationary phase. The absolute configurations of 4,5-dihydroxyhexanoic acid γ-lactones are assigned by 1H-NMR spectral data of diastereomeric α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) esters, according to Mosher's model. Sensory qualities of the isomers are given. 相似文献
986.
Shiro Tsuyuzaki 《Ecological Research》1989,4(2):167-173
In 1987, a study on buried seed populations was conducted in the crater basin of Mt. Usu, a volcano located in northern Japan,
where the vegetation had beeen almost completely destroyed by eruptions in 1977 and 1978. The former vegetation had consisted
of grassland and broad-leaved forest. In the areas formerly occupied by this grassland and forest, 2128.0 and 1985.3 seeds
per square meter, respectively, were extracted from 12 blocks of the former topsoil using a floattion method. This revealed
that many seeds were still viable even after ten years of burial under thick volcanic deposits. The seeds were distributed
more in sandy soil than in rocky soil of the former topsoil. Twenty-five species, most of which favored grassland, were detected
in both the former grassland and forest. From comparison of α-and β-diversities between the grassland and forest, the structure
of the buried seed population was considered likely to have been more diverse in the forest than in the grassland. The determinants
of composition of the buried seed populations were discussed with reference to the former vegetation and soil characteristics. 相似文献
987.
The authors examined relationships between Kira's warmth index (WI) and four other important thermal indices: the sums of
daily mean temperatures above 5°C and 10°C, Thornthwaite's potential evapotranspiration (PE) and Holdridge's annual biotemperature.
The thermal records of 671 meteorological stations evenly located all over China were used to make these comparisons. Close
correlations were found within the four relationships, and accordingly WI was used to analyse the thermal distributions of
the main vegetation types. Vegetation types around the 671 stations were read from a vegetation map with a scale of 1/4000000.
Vegetation types at 269 stations corresponded to the natural or seminatural vegetation, and 29 vegetation types were distinguished
by arranging the 269 data into the same or similar types. The geographical distribution of these 29 types and the corresponding
main climatic features were described. The relations between WI and distribution of these vegetation types were discussed
in detail. As a result, WI values (°C month) corresponding to the vegetation zones could be summarized as follows: (1) arctic
or alpine vegetation zone: 0–15; (2) boreal or subalpine vegetation zone: 15-(50–55); (3) cool-temperate vegetation zone:
(50–55)–(80–90); (4) warm-temperate vegetation zone: (80–90)–(170–180). These values almost coincided with Kira's values.
Chinese postgraduate student in Japan sent by the Chinese Government. 相似文献
988.
Anne Marpeau Jocelyne Walter Jacqueline Launay Jacqueline Charon Philippe Baradat Michel Gleizes 《Trees - Structure and Function》1989,3(4):220-226
Summary The effect of wounds on the volatile terpene composition of the living bark of Pinus pinaster Ait. (maritime pine) twigs was investigated with respect to the processes of mono- and sesquiterpene hydrocarbon biosynthesis. The large increase in the amounts of - and -pinene is a characteristic feature after a mechanical injury, whereas the quantities of the other terpenes are only slightly increased. This is due to the reactivation of the resin duct secretory cells of primary origin located in cortical tissues. The effect of wounding is observed over a long period and the terpene profiles are very different at the end of the experiments as compared with the initial profiles of the same tissues. The traumatic essential oil (obtained after mechanical traumatism) resembles an oleoresin extracted from tissues of secondary origin. Statistical analysis underlines the effects of the between-tree variations and of the dates of application of the wound. 相似文献
989.
P. K. Lauf 《The Journal of membrane biology》1990,118(2):153-159
Summary Hydroxylamine, a potent oxidizing agent used to reverse carbethoxylation of histidine by diethylpyrocarbonate, activated Cl-dependent K flux (KCl cotransport) of low K sheep red blood cells almost sixfold. When KCl cotransport was already stimulated by N-ethylmaleimide, hydroxylamine caused an additional twofold activation suggesting modification of sites different from those thiol alkylated. This conclusion was supported by the finding that hydroxylamine additively augmented also the diamide-induced KCl flux (Lauf, P.K. 1988.J. Membrane Biol.
101:179–188) with dithiothreitol fully reversing the diamide but not the hydroxylamine effect. Stimulation of KCl cotransport by hydroxylamine was completely inhibited by treatment with diethylpyrocarbonate also known to prevent KCl cotransport stimulation by N-ethylmaleimide, both effects being independent of the order of addition. Hence, although the effect of carbethoxy modification on KCl flux cannot be reversed by hydroxylamine and thus excludes histidine as the target for diethylpyrocarbonate, our finding reveals an important chemical determinant of KCl cotransport stimulation by both hydroxylamine oxidation and thiol group alkylation. 相似文献
990.
Summary To investigate molecular evolution in a mammalian order with a comprehensive fossil record, we have constructed-globin-like gene cluster maps for members of the order Perissodactyla. Although the arrangement of genes is the same in the five Equidae examined, the tapir and rhinoceros differ from each other and the horse in the position and number of their genes, but not in the arrangement of their and genes. In contrast to morphological work, a dendrogram derived from restriction site maps associates the tapir with the horse rather than with the rhinoceros; however, this phylogeny is not statistically significant. Among the Equidae,Equus caballus emerges as an outgroup, in agreement with data from other disciplines. 相似文献