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.     

Metabolism of papaverine. II. Species differences.

1. The urinary and biliary excretion of radioactive products in a 6 hr period after intravenous administration of [3H]papaverine was studied in rat, guinea-pig, rabbit, cat and dog. All species excreted metabolites extensively in the bile; only in rabbit and guinea-pig is urinary excretion important. 2. Metabolites in urine and bile of all species studied are mainly monophenolic compounds conjugated to glucuronic or sulphuric acid. Differences in the excretion patterns of the metabolites between different species are only quantitative. 3. Blood or plasma levels of papaverine after intravenous injection decreased with half-lives of approximately 12, 15, 22, 60 and 60 min for rabbit, rat, guinea-pig, cat and dog, respectively. The metabolites disappeared much more slowly than papaverine from the plasma. 4. Binding of papaverine to plasma proteins, as studied by equilibrium dialysis, was more than 90% in all species.