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Biomedical subjects

D Henschler

Publications and source records attributed to D Henschler.

At least 73 records · Page 4Linked to original sources
PubMed1986

Bacterial beta-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene and hexachlorobutadiene.

The metabolism of beta-lyase and the mutagenicity of the synthetic cysteine conjugates S-1,2-dichlorovinylcysteine (DCVC), S-1,2,2-trichlorovinylcysteine (TCVC), S-1,2,3,4,4-pentachlorobuta-1,3-dienylcysteine (PCBC) and S-3-chloropropenylcysteine (CPC) were investigated in Salmonella typhimurium strains TA100, TA2638 and TA98. The bacteria contained significantly higher concentrations of beta-lyase than mammalian subcellular fractions. Bacterial 100,000 X g supernatants cleaved benzthiazolylcysteine to equimolar amounts of mercaptobenzthiazole and pyruvate. DCVC, TCVC and PCBC produced a linear time-dependent increase in pyruvate formation when incubated with bacterial 100,000 X g supernatants; pyruvate formation was inhibited by the beta-lyase inhibitor aminooxyacetic acid (AOAA). CPC was not cleaved by bacterial enzymes to pyruvate. DCVC, TCVC and PCBC were mutagenic in three strains of S. typhimurium (TA100, TA2638 and TA98) in the Ames-test without addition of mammalian subcellular fractions; their mutagenicity was decreased by the addition of AOAA to the preincubation mixture. CPC was not mutagenic in any of the strains of bacteria tested. These results indicate that beta-lyase plays a key role in the metabolism and mutagenicity of haloalkenylcysteines when tested in S. typhimurium systems. The demonstrated formation in mammals of the mutagens DCVC, TCVC and PCBC during biotransformation of trichloroethylene (Tri), tetrachloroethylene (Tetra) and hexachlorobutadiene (HCBD) may provide a molecular explanation for the nephrocarcinogenicity of these compounds.

Animals↗
PubMed1986

Mutagenicity of chloroolefins in the Salmonella/mammalian microsome test--II. Structural requirements for the metabolic activation of non-allylic chloropropenes and methylated derivatives via epoxide formation.

Non-allylic chloropropenes and their methyl-homologues, being chloro-substituted exclusively in vinylic position, are mutagenic in the presence of metabolizing rat liver homogenate fraction (S9 mix). This can be interpreted as the result of polarizing inductive (I-) and mesomeric (M-) effects exerted by Cl- as well as by CH3-substituents on the olefinic double bond. The extent of their mutagenic activity increases with longer preincubation time and/or a higher concentration of rat liver homogenate fraction (S9) in the S9 mix. The only exception from this rule of a qualitative correlation of C = C-bond polarization due to asymmetric substitution and mutagenic activity is 1-chloro-2-methyl-1-propene which is non-mutagenic. In this case effects of a steric hindrance of two voluminous CH3-substituents attached to one C-atom of the C = C-bond might inhibit enzymatic attack of the double bond by microsomal oxygenase. Mutagenic activity is invariably decreased in the presence of SKF525, inhibitor of microsomal oxygenase, and increased when 1,1,1-trichloropropene-2,3-oxide (TCPO), inhibitor of epoxide hydrolase, is added to the test system. This is a strong argument for metabolic activation of these substances occurring via epoxide formation.

Alkenes↗
PubMed1986

Synthesis and genotoxicity of acetoxyoxirane, the epoxide of vinyl acetate.

Acetoxyoxirane, the epoxide of vinyl acetate and a potential reactive intermediate, was synthesized and characterized by 13C-nuclear magnetic resonance (13C-NMR) and mass spectroscopy. The compound induced lesions (endonuclease-sensitive and alkali-labile sites) in supercoiled PM2 DNA in vitro and was directly mutagenic toward Salmonella typhimurium TA100. The mutagenicity of the epoxide in phosphate buffer (pH 7.4, 37 degrees C) decreased, with an initial half-life of 2.8 minutes, and mutagenicity was completely abolished by addition of S-9 mix. Acetoxyoxirane did not induce unscheduled DNA synthesis on incubation with Syrian hamster embryo fibroblasts (SHE cells). These findings may possibly be explained by an effective inactivation of acetoxyoxirane by esterases when these are present in the biological system. This view is consistent with the lack of acetoxyoxirane detected in rat liver microsomal incubations of vinyl acetate.

Animals↗
PubMed1986

Identification of S-1,2,2-trichlorovinyl-N-acetylcysteine as a urinary metabolite of tetrachloroethylene: bioactivation through glutathione conjugation as a possible explanation of its nephrocarcinogenicity.

The elimination and metabolism of [14-C]-tetrachloroethylene (Tetra) was studied in female rats and mice after the oral administration of 800 mg/kg [14-C]-Tetra. Elimination of unchanged Tetra was the main pathway of elimination in both species and amounted to 91.2% of the dose in rats and 85.1% in mice. [14-C]-Carbon dioxide (CO2) was found to be a trace metabolite of [14-C]-Tetra. Only a small part of the applied dose was transformed to urinary (rats = 2.3%, mice = 7.1%) and fecal (rats = 2.0%, mice = 0.5%) metabolites. The urinary metabolites were separated and quantified by high performance liquid chromatography (HPLC) and identified by gas liquid chromatography/mass spectrometry (GC/MS). The following metabolites could be identified: oxalic acid (8.0% of urinary radioactivity in rats, 2.9% in mice), dichloroacetic acid (5.1%, 4.4%), trichloroacetic acid (54.0%, 57.8%), N-trichloroacetyl-aminoethanol (5.4%, 5.7%), trichloroethanol, free and conjugated (8.7%, 8.0%), S-1,2,2-trichlorovinyl-N-acetylcysteine (N-acetyl TCVC) (1.6%, 0.5%), and another conjugate of trichloroacetic acid (1.8%, 1.3%). The structures of the identified metabolites indicate two different pathways operative in Tetra biotransformation: cytochrome P-450-mediated epoxidation forming reactive metabolites in the liver and conjugation of Tetra with glutathione (GSH) catalyzed by glutathione transferase(s). The formation of reactive intermediates by renal processing of the glutathione conjugates may provide a molecular mechanism for the nephrotoxicity and nephrocarcinogenicity of Tetra in male rats.

Acetylcysteine↗
PubMed1986

Modulation of benzo[a]pyrene-induced morphological transformation of Syrian hamster embryo cells by butylated hydroxytoluene and butylated hydroxyanisole.

The Syrian hamster embryo cell transformation assay has been used to investigate the effect of two synthetic antioxidants on morphological transformation induced by the initiator benzo[a]pyrene (BP). A two-stage protocol was employed with an initiation phase of 2 days and a subsequent promotion phase of 5 days. When 10 microM butylated hydroxytoluene (BHT) were present in the promotion phase instead of the solvent the transformation frequency at 0.1 micrograms BP/ml increased from 0.27% to 0.55%; at 100 microM of BHT the transformation frequency was 0.77%. Butylated hydroxyanisole (BHA) also enhanced the percentage of transformed colonies from 0.40% (10 microM) to 0.49% (100 microM), respectively. No significant initiating activity was detected for both antioxidants when tested in the initiation phase instead of BP; when the antioxidants were applied simultaneously with BP (1 microgram/ml) during the initiation phase the transformation frequency was decreased from 0.64% to 0.15% (100 microM BHT) and to 0.17% (100 microM BHA), respectively. These results show that the dual action of phenolic antioxidants on chemical carcinogenesis, which depends on the administration schedule, can be imitated in an in vitro test system. In addition to their anti-initiation effect, BHT and BHA, while devoid of intrinsic initiator potency, exert a moderate promotional activity on hamster embryo cell cultures. Their ability to enhance tumorigenesis by various carcinogens in vivo is likely to be at least partially related to such promotion-like effects on cell growth and morphology.

Animals↗
PubMed1986

Absorption, elimination and metabolism of trichloroethylene: a quantitative comparison between rats and mice.

The absorption, elimination and metabolism of 14C-trichloroethylene (Tri) was studied in adult female Wistar rats and NMRI mice after administration of 200, 20 and 2 mg/kg Tri. Dose-dependent biotransformation of Tri to metabolites was observed in both species. Induction of hepatic mono-oxygenases by phenobarbital or polychlorinated biphenyls resulted in a higher rate of biotransformation after a single oral dose of 200 mg/kg 14C-Tri to rats. An increase in radioactivity covalently bound to liver and kidney macromolecules of induced rats as compared to control rats parallels the toxic effects of Tri on these organs after induction of cytochrome P-450. The urinary metabolites were analysed by h.p.l.c. In both species, 1,1,1-trichlorocompounds (trichloroacetic acid, trichloroethanol and its glucuronide, comprising 88.9-93.5% of the radioactivity excreted in the urine) constituted the main metabolites; in addition, N-(hydroxyacetyl)-aminoethanol (4.1-7.2%), dichloroacetic acid (0.1-2.0%) and oxalic acid (0.7-1.8%) were identified. The pattern of metabolites in the 72 h urine remained constant for each species in the dose range studied and no change was induced by pretreatment. The percentage of radioactivity exhaled as 14CO2 increased with dose in mice, which may indicate dose-dependent formation of dichloroacetic acid and saturation of deactivating mechanisms for reactive intermediates in mice.

Animals↗
PubMed1986

Structure-activity relationships of alpha, beta-unsaturated carbonylic compounds.

The mutagenicity and probably the carcinogenicity of alpha, beta-unsaturated carbonylic compounds such as acrolein are based on direct genotoxic interaction with nucleic acid bases via Michael addition or Schiff's base formation. Alkyl and aryl substitution at the alpha and beta carbon atoms reduces or abolishes the mutagenic potential whereas halogen substitution in either position increases mutagenicity. These structure-activity relationships can be predicted from theoretical considerations of well-known electron shift mechanisms. The formation of alpha, beta-unsaturated carbonyls from allylic halides (or similar types of compounds with appropriate leaving groups) has been experimentally demonstrated with appropriate metabolites of allyl bromide in in rats.

Acrolein↗
PubMed1985

Mutagenic activity in rat urine after feeding with the azo dye tartrazine.

The azo dye tartrazine, after dosing by gavage, is transformed by rats into urinary metabolites which exert dose-dependent mutagenic activities in the Ames test with Salmonella typhimurium TA 98 after addition of rat liver metabolizing enzymes (S9 mix). The strain TA 100 showed no mutagenic response.

Animals↗
PubMed1985

Morphological transformation of Syrian hamster embryo fibroblasts by the anabolic agent trenbolone.

Trenbolone (TBOH), a synthetic androgen used as an anabolic agent in livestock, has been tested for mutagenicity in the Salmonella assay, for covalent DNA-binding in vitro, for induction of unscheduled DNA synthesis in HeLa cells and Syrian hamster embryo (SHE) fibroblasts and for morphological transformation of SHE cells. While TBOH gave negative results in the assays for mutagenicity and DNA damage, it was clearly capable of transforming SHE cells in culture. The natural androgen testosterone did not transform these cells. Thus, TBOH appears to be a substance which can transform cells independent of its hormonal action and without grossly damaging DNA.

Animals↗
PubMed1984

Novel metabolites of trichloroethylene through dechlorination reactions in rats, mice and humans.

The excretion and biotransformation of [14C]trichloroethylene (Tri) has been studied in female rats and mice. Seventy-two hours after a single oral dose of 200 mg/kg, rats exhaled 52% and mice 11% of the recovered radioactivity as unchanged Tri, and 1.9% and 6%, respectively, as 14CO2. Rats excreted 41.2% of the recovered radioactivity in the urine, in contrast to mice where urinary activity amounted to 76%. The isolation of urinary metabolites was accomplished by reversed-phase HPLC, using a water-methanol gradient. After chemical derivatization, a combination of radio-GC and GC/MS was used for identification. The metabolites identified in rat urine were: trichloroacetic acid (15.3%); trichloroethanol, free (11.7%) and as the glucuronide (61.9%); dichloroacetic acid (2.0%); oxalic acid (1.3%) and N-(hydroxyacetyl)-aminoethanol (HAAE) (7.2%). In mice, trichloroethanol (free and in several conjugated forms) is the main metabolite of Tri (94.3%), but small amounts of HAAE (4.1%) and oxalic acid (0.7%) are also excreted. Only traces of dichloro- and trichloroacetic acids were found in this species. In human male subjects, HAAE was also identified as a urinary metabolite of Tri after exposure of two volunteers to 200 ppm Tri for 6 hr. The identification of HAAE and oxalic acid as metabolites indicates hydrolytic dechlorination reactions in the metabolism of Tri.

Administration, Oral↗