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Previous study demonstrated that the administration for several days of 1-(o-chlorphenyl)-1-(p-chlorophenyl)-2,2,2-trichloroethane (o,p'DDT) (estrogenic DDT derivative) or of tamoxifen (antiestrogen), but not of 2,2-bis-(p-chlorophenyl)-1,1-dichloroethylene (p,p'DDE) (nonestrogen), to ovariectomized female rats dramatically diminished the induction of uterine ornithine decarboxylase (ODC) by subsequently administered estradiol [W. H. Bulger and D. Kupfer, Archs Biochem, Biophys. 182, 138 (1977)]. The present investigation examines whether the inhibition of ODC induction by o,p'DDT and tamoxifen may have been due to enhanced hydroxylation of estradiol by the hepatic monooxygenase system. Additionally, the effects of other estrogenic and nonestrogenic xenobiotics on the major route of estradiol metabolism (2-hydroxylation) were examined. Treatment of ovariectomized (ovex) rats with o,p'DDT or p,p'DDE caused induction of hepatic estradiol-2-hydroxylation and increased demethylase activities of several substrates. Administration of Kepone (estrogenic) and Mirex (nonestrogenic), both inducers of hepatic monooxygenase, also increased 2-hydroxylation of estradiol. For comparative purposes, the effects on estradiol-2-hydroxylation of administration of classical estrogens (estradiol and diethylstilbestrol) and antiestrogen (tamoxifen) and inducers of monooxygenase activity (phenobarbital and 3-methylcholanthrene) were also studied. Treatment of ovariectomized and adrenalectomized (ovex/adx) or intact female rats with estradiol or ovex/adx animals with diethylstilbestrol had no effect on estradiol-2-hydroxylation. Similarly, tamoxifen did not alter the rate of estradiol-2-hydroxylation. The treatment of ovex/adx rats with 3-methylcholanthrene did not affect the rate of estradiol-2-hydroxylation. By contrast, ovex/adx female or intact male rats treated with phenobarbital exhibited induction of estradiol-2-hydroxylase activity. In the above studies only 2-hydroxyestradiol was found; there was no evidence for the formation of primary metabolites hydroxylated at other sites on estradiol. The current findings exclude the possibility that the previously observed inhibition of estradiol-mediated induction of ODC by pretreatment with o,p'DDT or tamoxifen (see article cited above) was due to enhanced hydroxylation of estradiol by liver monooxygenases. Also, it was concluded that there is no correlation between the ability to induce hepatic microsomal estradiol-2-hydroxylase activity and estrogenic (or antiestrogenic) properties of a given compound.
The crystal of "methyl C-gentiobioside" (methyl 8,12-anhydro-6,7-dideoxy-D-glycero-D-gulo-alpha-D-gluco-trideca pyranoside) (C14H26O10) is triclinic, space group P1, with a = 1.0181 (6) nm, b = 0.8093 (5) nm, c = 0.5066 (4) nm, alpha = 96.03 (5) degrees, beta = 99.94 (5) degrees, gamma = 90.85 (5) degrees. The two D-glucose residues have the 4C1 conformation. The orientation of the beta-(1----6) linkage is characterized by torsion angles phi = 55.9 degrees, psi = 175.1 degrees, and omega = -63.9 degrees. The orientation of the primary hydroxyl group at the non-reducing residue is gauche-trans (omega' = -53.6 degrees). There is no intramolecular hydrogen bond. Molecules are held together by a network of hydrogen bonds involving all of the hydroxyl groups. This crystal structure is the first experimental characterization of a "C-disaccharide". Unlike methyl gentiobioside, which has a high level of conformational flexibility, the "C-disaccharide" has a restricted flexibility. Each of the low-energy conformers in vacuo has a value of phi centered about 60 degrees, in agreement with the solid state conformation, and the exo-anomeric effect is no longer predominant.
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The mutagenicity of several K-region arene oxides was tested in histidine-dependent mutants of Salmonella typhimurium. Benzo(a)pyrene-4,5-oxide and pyrene-4,5-oxide as well as some substituted phenanthrene oxides were mutagenic in strains TA 1538 and TA 98 which detect frame-shift mutagens. Structure-activity relationships are discussed from the standpoint of chemical reactivity. The absence of direct correlation between electrophilic reactivity and mutagenicity may suggest that primilarily physical properties, such as relative position of the epoxide group and molecular shape of arene oxides, are important for the emergence of mutagenicity of arene oxides.
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1. The cardiovascular selectivities of 1,4-dihydropyridine derivatives, efonidipine (NZ-105), nicardipine, 3NZ5NIC (the drug with NZ-105-type side-chain at C3 position and nicardipine-type at C5) and 3NIC5NZ (the drug with nicardipine-type side chain at C3 and NZ-105-type at C5) were studied in vitro. 2. All four compounds caused relaxation of guinea-pig aortae precontracted with a high K+. The pEC50 values were 7.5, 8.3, 8.1 and 5.6, for NZ-105, nicardipine, 3NIC5NZ and 3NZ5NIC, respectively. The relaxation produced by NZ-105 was slower in onset than those produced by the other compounds. The rate constant K(hr-1) of the relaxations were 0.59, 1.31, 1.02 and 1.24, for NZ-105, nicardipine, 3NIC5NZ and 3NZ5NIC, respectively. 3. In the electrically paced guinea-pig papillary muscles, NZ-105, 3NIC5NZ and 3NZ5NIC, even at concentrations as high as 10(-6) M, slightly decreased the contractile force (by 44.9 +/- 7.1%, 58.6 +/- 5.4% and 52.2 +/- 3.9%, respectively), whereas 10(-6) M nicardipine decreased the force by 84.9 +/- 3.3%. The negative inotropic effect of NZ-105 and 3NIC5NZ, but not that of 3NZ5NIC or nicardipine, was over 10 times weaker than their vasorelaxant effect. 4. In the guinea-pig right atria, NZ-105 and nicardipine at 10(-8) M decreased the spontaneous contraction rate by 67.9 +/- 15.0% and 39.7 +/- 15.4%, respectively. 3NIC5NZ at 3 x 10(-9) M and 3NZ5NIC at 3 x 10(-8) M had little effect on the rate, whereas 10(-8) M 3NIC5NZ and 10(-7) M 3NZ5NIC arrested the beating within 3 hr after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Emerging resistance to the current fluoroquinolones has encouraged synthesis of new compounds in this class. We have evaluated the activity of DU-6859a, a novel halogenated quinolone, against a panel of 300 bacteria, relative to the activity of ciprofloxacin, clinafloxacin, fleroxacin, levofloxacin, ofloxacin, and sparfloxacin. DU-6859a was the most active of the fluoroquinolones studied and retains potentially useful activity against 80% of isolates resistant (minimum inhibitory concentration, > or = 4 micrograms/ml) to ciprofloxacin. Continued clinical investigation of DU-6859a and similar new quinolones is urged.
Glycoasparagines obtained after exhaustive digestion by Pronase of purified ovalbumin were partially degraded by trifluoroacetic acid or subjected to Smith degradation. The partially degraded glycoasparagines thus obtained were first fractionated according to molecular size on Dowex 50W-X2 and then further fractionated by borate chromatography on a column of Sephadex A-25. For a mixture of glycoasparagines of similar molecular size, the latter procedure fractionates according to increasing content of mannosyl cis-2,3-diol. Ten fragment glycoasparagines have been prepared from ovalbumin glycoasparagines, and the structures determined by 1H-n.m.r. spectroscopy and methylation analysis.
Binding of diethylstilbestrol and four different triphenylethylene derivatives: tamoxifen, toremifene, clomiphene and triparanol to DNA in rat liver, was studied using the 32P-postlabelling method with HPLC-radioactivity detection. Three different modifications of the 32P-postlabelling technique (a) a bisphosphate method with adduct enrichment by nuclease P1 (NP1)-treatment or (b) by butanol extraction and (c) a monophosphate method, were applied in order to provide an unbiased analysis of adduct formation. When tamoxifen was administered by daily gavage for 4 weeks (80 mumol/kg for 2 weeks and 40 mumol/kg for a further 2 weeks) two major adducts and about six minor adducts were produced in the liver of female Sprague-Dawley rats. Equimolar doses of toremifene produced one apparent adduct. The adduct levels in the tamoxifen and toremifene treated rats were 600 and 2/10(8) nucleotides, respectively. Under conditions used, clomiphene, triparanol and diethylstilbestrol did not produce DNA adducts. The present and previous data suggest that modification (a) is the 32P-postlabelling method of choice for risk assessment in human subjects. Modification (c) with butanol extraction after labelling has the advantage of low background radioactivity and may be preferable if large amounts of DNA are available. The main tamoxifen adducts were suggested to be alpha-(N2-deoxyguanosinyl)tamoxifen and alpha-(N2-deoxyguanosinyl)-N-desmethyltamoxifen.