Trichloroethylene. I. Carcinogenicity of trichloroethylene.

Trichloroethylene (TCE) as an industrial pollutant may damage human health and can be considered as carcinogen. TCE has been detected in the environment and in various human organs, e.g., liver, kidney and brain etc. There are histological alterations such as depletion of glycogen and hydropic degeneration in the liver, however, other signs of TCE effects can be found in various organs as well. TCE and its metabolites, e.g., trichlorethanol, trichloro-acetic acid and epoxides were recently identified as strong mutagens in Ames mutagenicity test inducing frameshift and base-substitution mutations. TCE induced predominantly hepatocellular carcinoma after long term administration in mice. In these animals, kidneys and liver were supposed to be primary target organs with low epoxy-hydrolase activity. A high level of mitotic gene conversion (or gene rearrangement) was indicated by the metabolism of TCE after repeated administration. Purified TCE by was a weak mutagen in the presence of S9 microsomal fraction of rats and as a consequence, the carcinogenic activity was low in the kidney of rats. However, a dose related increase of Leydig cell tumors was found in male rats.     

Trichloroethylene. II. Mechanism of carcinogenicity of trichloroethylene.

The cancer inducing effect of trichloroethylene (TCE) was studied by various methods. DNA complexing activity and apoptosis inhibition were found to be the key elements of the carcinogenicity of TCE and its metabolites. The ability of TCE to interact with DNA was low, but its incorporation into the RNA and DNA of the brain, testis, pancreas, kidney, liver, lung and spleen, cannot be excluded. Exposure to TCE and its metabolites provides a selective growth advantage to spontaneously occurring mutations in some K- and H-ras oncogenes (as non specific results of secondary DNA or RNA damage). The amount of DNA-TCE adducts was higher in mouse hepatocytes than in rat hepatocytes. These differences may explain the species difference in carcinogenicity of TCE, which was dose dependent (due to metabolism) in mice but independent in rats. The blood level kinetics of TCE confirmed the faster metabolic rate in mice, including peroxisome proliferation and induction in hepatocytes. Dichloroacetic- and trichloroacetic acid were found to be hepatic carcinogens in mice, and the specificity depends on peroxisome proliferation induction. Possibly, TCE and related compounds down regulated apoptosis in mouse liver, and the reduced ability to remove initiated cells by apoptosis could be responsible for liver cancer induction by TCE.     

Studies in antifertility agents. 11. Secosteroids. 5. Synthesis of 9,11-secoestradiol.

9,11-Secoestradiol (9) and 11-hydroxy-9,11-secoestradiol (12) have been synthesized starting from 17-acetoxyestradiol 3-methyl ether (1) and found to possess significant antifertility activity in rats. 3-Methoxy-9,11-seco-9-oxo-17beta-acetoxyestra-1,3,5(10)-trien-11-oic acid (2), prepared by CrO3 oxidation of 1, on hydrogenolysis gave methyl 17beta-hydroxy-3-methoxy-9,11-secoestra-1,3,5(10)-triene-11-carboxylate (3). The 17-O-THP derivative of 3 was treated with LiAlH4 to give 17beta-(O-tetrahydropyranyl)-3-methoxy-11-hydroxy-9,11-secoestra-1,3,5(10)-triene (5). The 11-O-mesylate of 5 on LiAlH4 reduction followed by mild acid treatment and demethylation under alkaline conditions gave 9. LiAlH4 reduction of 3 gave 9,11-seco-11-hydroxyestradiol 3-methyl ether (11) which on demethylation gave 9,11-seco-11-hydroxyestradiol (12).     

Metabolism of benzothiazole. I. Identification of ring-cleavage products.

1. The metabolic fate of benzothiazole in guinea pig has been investigated following i.p. administration at a dose of 30 mg/kg. 2. Five ring-cleavage products were identified in urinary extracts by g.l.c.-mass spectra. By reference to authentic compounds the three major metabolites were shown to be 2-methylmercaptoaniline (I), 2-methylsulphinylaniline (II) and 2-methylsulphonylaniline (III). On the basis of the mass spectrometric evidence the remaining two metabolites were postulated to be 2-methylsulphinylphenylhydroxylamine (IV) and 2-methylsulphonylphenylhydroxylamine (V). 3. I, II and III were present in conjugated and unconjugated forms; IV and V were identified only after hydrolysis with sulphatase.     

Discussion of S.G. Donald et al. and R. Davidson

Summary This paper discusses aspects of the papers by S.G. Donald et al. and R. Davidson, which were presented at The Econometrics Journal sponsored special session on the econometrics of inequality measurement, held at the Royal Economics Society Meeting in Surrey in 2010.     

Oxygen-17 n.m.r. of peptides

Peptide-¹⁷O chemical shifts of linear dipeptides with and without protecting groups in H₂O, CH₃OH, CH₂Cl₂, CHCl₃, CCl₄, CH₃CN and DMSO were between 256–350 ppm downfield from external water. Increasing solvent H-bond donating ability correlated with shifts to higher field. The ¹⁷O resonance of several cyclic dipeptides appeared at higher field relative to comparable linear dipeptides (303–317 p.p.m. vs. 327–337 p.p.m.). Separate signals were simultaneously observed by ¹³C and ¹⁷O n.m.r. for cis and trans N-tert.-butyl-formamide in binary mixtures with H₂O, (CH₃)₂CO, and CCl₄. The differences in the ¹⁷O nuclear screening of the amide isomers and most probably for cis and trans peptides were independent of contributions from H-bonding at the amide or peptide linkage, apparently reflecting differences between geometric isomers in electron distribution and through space effects. Peptide-¹⁷O of Gly-Ala, Gly-Leu and Gly-Glu in aqueous solution experienced upfield shifts of 6–12 p.p.m. and 12–16 p.p.m. upon deprotonation of the C-terminal COOH and of the N-terminal NH+₃ groups respectively. These observations were rationalized in terms of the attendant changes in substituent effects, especially on the ± electron donating ability of the N atom at the peptide linkage and increased partial negative charge on the peptide oxygen. Temperature studies of peptide-¹⁷O of Gly-Ala between pH 1.5–9.0 revealed a chemical shift coefficient of 0.08 p.p.m./K and similar behavior of T₁ and T₂ relaxation times. Ea for molecular rotation was 5 kcal/mol between 301–331·K. Rotational correlation times, _c, were within the range expected from the Stokes-Einstein relation.