Inhibition of DNA synthesis in relation to enhanced survival of UV-damaged herpes virus in monkey cells treated by a variety of 2-nitronaphthofurans

Various 2-nitronaphthofuran derivatives (related to each other by simple structural modifications) were tested for 2 different effects in CV-1 monkey kidney cell cultures: the immediate inhibition of normal DNA synthesis and the capacity of pretreated cultures (40 h of contact) to support the replication of UV-damaged Herpes simplex virus (HSV). For all compounds tested, a fair correlation was found between their efficiencies to inhibit cellular DNA synthesis and to provoke an increase in UV-HSV production (virus reactivation). Virus reactivation was due to an increase in both the number of virus-producing cells and the amount of infectious particles produced per cell. The most efficient 2-nitronaphthofurans (particularly 2-nitro-7-methoxy-naphtho[2,1-b]furan-R 7000) were at least as potent as aflatoxin B1 in inducing virus reactivation.     

Interaction of diphtheria toxin fragment A and of elongation factor 2 with Cibacron blue

Diphtheria toxin fragment A interacts with Cibacron blue in solution, although it is not retained by blue Sepharose columns. Difference spectral titration of fragment A with the dye gives a dissociation constant of the order of 10^–5 M and a 11 stoichiometry for the complex. In equilibrium dialysis experiments Cibacron blue behaves as a competitive inhibitor of the binding of NAD to diphtheria toxin fragment A. The dye inhibits in a non-competitive way the fragment A-catalysed transfer of ADP-ribose from NAD to elongation factor 2 (EF2). By affinity chromatography on blue Sepharose a binding of EF2 and of ADP-ribosyl-EF2 with the dye is also demonstrated. GDP, GTP and GDP(CH₂)P are able to displace EF2 from blue Sepharose.     

Evaluation of the genotoxic activity of 2-nitroanthrafurans

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS chromotest (an assay for SOS induction in E. coli), of three 2-nitroanthrafurans: 2-nitroanthra[1,2-b]furan (R-7688), the isomeric compound 2-nitroanthra[2,1-b]furan (R-7686) and its 8-methoxylated derivative (R-7707). Their genotoxic activities were compared to that of 7-methoxy-2-nitronaphtho[2,1-b]furan (R-7000) which has been studied in previous works (Arnaise et al., 1986). We found that: (1) for all three 2-nitroanthrafurans, as generally observed for other 2-nitrofuran derivatives, the responses were correlated in the 2 tests and were decreased in the presence of an 'activating mixture' and in nitroreductase-deficient strains; (2) in contrast to what is usually observed with other 2-nitrofuran derivatives for which methoxylation increases genotoxic activity, the genotoxic activity of the methoxylated 2-nitroanthrafuran (R-7707) was comparable and may be even lower than that of the unsubstituted 2-nitroanthrafuran (R-7686); (3) the addition of a third ring that leads from 2-nitronaphthofurans to 2-nitroanthrafurans increased slightly the genotoxic activity of these compounds; (4) compounds with the oxygen heteroatom outside the 'bay region', R-7686 and R-7707, gave higher responses than their isomers with the oxygen heteroatom within the 'bay region', R-7688.     

The gene for X-linked hydrocephalus maps to Xq28, distal to DXS52.

We report the study of five independent X-linked hydrocephalus (HSAS1) families with polymorphic DNA markers of the Xq28 region. A total of 58 individuals, including 7 living affected males and 22 obligate carriers, have been studied. Maximum lod score was 7.21 at theta = 2.40% for DXS52 (St14-1). A single recombination event was observed between this marker and the HSAS1 locus. Other markers studied were DXS296 (Z = 2.02 at theta = 2.5%), DXS304 (Z = 4.37 at theta = 7.8%), DXS74 (Z = 3.50 at theta = 0%), DXS15 (Z = 1.96 at theta = 5.7%), DXS134 (Z = 3.31 at theta = 0%), and F8C (Z = 5.79 at theta = 0%). These data confirm the localization of the HSAS1 gene to Xq28 and provide evidence for genetic homogeneity of this syndrome. In addition, examination of two obligate recombinant meioses along with multipoint linkage analysis supports the distal localization of the HSAS1 locus with respect to the DXS52 cluster. These observations are of potential interest for future studies aimed at HSAS1 gene characterization.     

Genotoxic activity of two furan analogues of benzo[a]pyrene and their 2-nitro derivatives

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS Chromotest (an assay for SOS induction in E. coli), of two pairs of isomeric furan analogues of benzo[a]pyrene: pyreno[1,2-b]furan (R7490) and pyreno[2,1-b]furan (R7692) and their 2-nitro derivatives, 8-nitro-pyreno[1,2-b]furan (R7489) and 8-nitro-pyreno[2,1-b]furan (R7691). We found that: For all 4 compounds, the responses were correlated in the two tests. For the 2-nitro derivatives, R7489 and R7691, the responses were extremely high, reaching SOS-inducing potencies of 5.2 X 10(3) and 10(5)/nmole in the SOS Chromotest and mutagenic potencies of 6.3 X 10(4) and 3.7 X 10(7) revertants/nmole in the Salmonella/histidine assay (strain TA98), respectively; the responses were only slightly decreased in nitroreductase-deficient strains. The responses to the two pyrenofurans were increased in the presence of an "activating mixture" but were still lower than that to benzo[a]pyrene. In contrast to benzo[a]pyrene and pyreno[2,1-b]furan (R7692), pyreno[1,2-b]furan (R7490) also gave a response in the absence of an "activating mixture". (5) Compounds with the oxygen heteroatom within the "bay region" gave lower responses than their isomers with the oxygen heteroatom outside the "bay region".     

Inhibition of polyphosphoinositide phosphodiesterase by aminoglycoside antibiotics

The calcium-activated phosphodiesteratic hydrolysis of³²P-labeled phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate in prelabeled nerve ending membranes is inhibited by the aminoglycosides neomycin and gentamicin, and to a lesser extent, by streptomycin. The inhibition is overcome by increasing concentrations of Ca²⁺, indicating that the aminoglycosides exert their effect by displacing Ca²⁺ from lipid.Dedicated to Professor Yasuzo Tsukada.     

Increased GH responsiveness to dopamine receptor stimulation in alcohol addicts during the late withdrawal syndrome

In humans the release of growth hormone (GH) elicited by dopamine (DA) and DA agonists may represent a reliable model to assess change in sensitivity of DA receptors. We now report that in chronic alcoholics, 4–7 days after the suspension of alcohol consumption, the increase of GH response to DA infusion was higher than that seen in non alcoholic volunteers. The specificity of this GH response to DA administration was demonstrated by the use of domperidone, a novel peripheral antagonist of DA receptors. These results suggest the development of hyper-responsiveness of DA receptors involved in the control of GH secretion in chronic alcoholics during the later phases of the “withdrawal syndrome”.