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At least 19 recordsLinked to original sources
PubMed1979

Microsomal target proteins of metabolically activated aromatic hydrocarbons.

The specificity of binding to microsomal proteins of metabolically activated hydrocarbons has been studied. Radioactively labelled benzene, phenol, chlorobenzene, BP and MC were incubated with liver microsomes from control, phenobarbital- and MC-treated rats in the presence of an NADPH-generating system. The patterns of metabolite binding to microsomal proteins were examined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and fluorography. Benzene, phenol and chlorobenzene metabolites showed one type of binding pattern dominated by a band at 72 000 Mr. This band was strong both in control and induced microsomes. Additional radioactive bands were seen in the 50 000--60 000 Mr region particularly in MC-induced microsomes. BP and MC metabolites showed a different type of binding pattern with incorporation of radioactivity into several fractions in the 50 000--60 000 Mr region of MC-induced microsomes. Two other strongly labelled fractions occurred at 68 000 and 72 000 Mr. The incorporation was low into control and phenobarbital-induced microsomes. Two labelled bands (Mr 56 000 and 72 000) were common for all hydrocarbons in MC-induced microsomes. The 56 000 Mr band had the same mobility in the gel as an MC-induced protein likely to be cytochrome P-448. The NADPH-generating system was essential for metabolite binding and GSH and UDPGA greatly reduced binding. We suggest that differences in metabolite binding patterns reflect differences in the routes of metabolite formation and that activated hydrocarbons are likely to bind to proteins close to their site of formation.

Animals↗
PubMed1978

The in vitro metabolism of lindane by an enzyme preparation from chicken liver.

The soluble fraction (105,000 x g, 30 min) of chicken liver homogenates contained an enzyme(s), probably a dehydrochlorinase(s), which metabolized lindane in vitro. The reaction was glutathione dependent and took place anaerobically. The enzyme(s) also metabolized the alpha- and delta-isomers but not the beta-isomer. About 66% of the in vitro metabolites were soluble in petroleum ether. From the ether-soluble fraction, o-, p- amd m-dichlorobenzene, 1,2,3- and 1,2,4-trichlorobenzene, gamma-2,3,4,5,6-pentachlorocyclohex-1-ene (gamma-PCCH), 2,3- and 2,4-dichlorophenol and 2,4,6-trichlorophenol were identified by comparison of mass spectra and gas chromatographic data with those of reference compounds. Seven additional metabolites were tentatively identified from their mass spectra data. These metabolites were: chlorobenzene, 2 isomers of trichlorocyclohexene, dichlorocyclohexadienetriol, chlorophenol, trichlorocyclohexenol and trichlorocyclohexanediol. The petroleum ether-extracted aqueous phase contained a number of unidentified conjugated metabolites. It was concluded that the metabolic pathway for lindane in the chicken is quite similar to that in the pheasant.

Animals↗
PubMed1979

Iodosylbenzene derivatives as oxygen donors in cytochrome P-450 catalyzed steroid hydroxylations.

The mechanism of cytochrome P-450 catalyzed steroid hydroxylations in rat liver microsomes has been investigated by employing derivatives of iodosylbenzene as oxygen donors. The model steroid substrate androstenedione which was hydroxylated in positions 7 alpha, 6 beta, and 16 alpha was used in reactions supported by NADPH, iodosylbenzene, and iodosylbenzene derivatives. Evidence for cytochrome P-450 involvement in iodosylbenzene-sustained androstenedione hydroxylation included inhibition by substrates and modifiers of cytochrome P-450. The most efficient oxygen donors were (diacetoxyiodo)-2-nitrobenzene greater than (diacetoxyiodo)-2-chlorobenzene greater than 2-nitroiodosylbenzene greater than (dinitratoiodo)-2-nitrobenzene greater than (diacetoxyiodo)benzene greater than (diacetoxyiodo)-2-methoxybenzene greater than 4-(diacetoxyiodo)toluene greater than iodosylbenzene. The capacity of the oxidation agents to serve as oxygen donors in cytochrome P-450 dependent steroid hydroxylation is probably dependent upon several factors such as the tendency of iodosyl compounds to associate, which decreases coordination with the heme iron, the presence of bulky substituents in the 2 position (decreases association), and the presence of electron-withdrawing substituents (tends to decrease coordination with the heme iron). The rates of 7 alpha, 6 beta, and i6 alpha hydroxylation of androstenedione catalyzed by (diacetoxyiodo)-2-nitrobenzene were 108-, 130-, and 167-fold higher, respectively, than the rates of the NADPH-supported reactions. These results strongly suggest that the rate-limiting step in NADPH-sustained cytochrome P-450 catalyzed reactions is the rate of reduction of cytochrome P-450.

Androstenedione↗
PubMed1976

Residues of lindane and its metabolites in eggs, chicks, and body tissues of hen pheasants after ingestion of lindane-14C via treated wheat seed or gelatin capsules.

Studies were carried out to investigate possible contamination of pheasants with residues of lindane used as seed dressings for the control of wireworms in cereal crops. One group of laying hen pheasants was fed 20 mg of lindane-14C in gelatin capsules while another group was fed wheat seed treated with 100 ppm of lindane-14C for 15 days. Residues in eggs were monitored for about 70 days. Residues in chicks hatched from the eggs were also measured. Concentrations of residues in muscle, liver, brain, and fatty tissues were determined at various times. 14C-labeled residues in eggs increased sharply in the capsule treated group and reached an average maximum of about 19 ppm in 8 days. This level decreased to less than 0.5 ppm in about 50 days. Residues in eggs from the pheasants fed treated seed increased gradually to an average maximum of 17 ppm 22 days after commencement of the feeding program. This level decreased to less than 0.5 ppm 50 days later. Residues in hatched chicks were significantly lower than those in the eggs. Highest concentrations of residues were found in fatty tissues which decreased to non-detectable level in 6 months. Several chlorobenzene metabolites were identified in egg yolk and chick tissues. Chlorophenolic metabolites were indicated only in chicks.

Animals↗
PubMed1977

The absorption, excretion and plasma protein binding of lofepramine in the rat, dog and man.

1. Lofepramine labelled with 3H in the dihydrodibenzazepine moiety and 14C in the chlorobenzene moiety was given orally to rats (20 mg/kg), dogs (3 mg/kg) and man (2 mg/kg).2. In dogs and man blood isotope levels were determined by combustion. In both species the 14C-levels were higher than the 3H-levels during the first 6 h after dosing. Later more 3H was found. 3. In all three species most of the 14C activity was rapidly excreted in the urine as the glycine conjugate of p-chlorobenzoic acid. 4. No significant species difference in the urinary excretion of 3H-labelled metabolites was found and the major metabolites were 2-hydroxydesmethylimi pramine, 2-hydroxyiminodibenzyl and desmethylimipramine. 5. Considerable amounts of desmethylimipramine were found in faeces of dog and man but not rat. This differnece is discussed. 6. By the ultrafiltration technique, lofepramine was found to be bound to plasma proteins of the rat, dog and man to an extent of 99%.

Adult↗
PubMed1978

Glutathione conjugation of some xenobiotics by Ascaris suum and Moniezia expansa.

1. The cestode Moniezia expansa and the nematode Ascaris suum both possess enzymes catalysing the conjugation of glutathione (GSH) with 1-chloro-2,4-dinitrobenzene. 2. The GSH-S-aryl transferase (GSH-S-transferase A) was present in the cytosol of the cestode proglottids and of the nematode intestinal epithelial cells. Other tissues did not contain measurable activity. The enzymes from both species had mol. wt. of about 37 000 and broad pH optima around pH 8.3. Both enzymes were inhibited by Cu2+, Fe3+ and Hg2+ at 1 mM and stimulated by Co2+. 3. Neither M. expansa nor A. suum possessed measurable DDT dehydrochlorinase activity. GSH-S-epoxide transferase (GSH-S-transferase E) activity was indicated in both species; neither species effected the conjugation of bromo- or chlorobenzene. 4. Halogenated anthelmintics were not metabolized to GSH conjugates in the helminths studied and did not inhibit GSH-S-aryltransferase activity towards chlorodinitrobenzene.

Animals↗
PubMed1978

[Chemical and pharmaceutical research on pyran derivatives. X. Synthesis of 1-oxo-2-alkyl-3-dialkylamino-1H-naphtho[2,1b]pyrans].

When reaction of N,N-dialkyl-alpha-ethoxycarbonyl-alpha-alkylacetamides with beta-naphthol in the presence of phosphorus oxychloride was carried out in chlorobenzene at reflux, formation of 1-oxo-2-alkyl-3-dialkyl-amino-1H-naphtho[2,1-b]pyrans was achieved together with some other products whose structure was defined. Moreover, substitution of the 2 position of 1-oxo-3-dialkylamino-1H"naphtho[2,1-b]pyrans with chlorine or cyano group as well as the preparation of 1-thio-3-dialkylamino-1H-naphtho[2,1-b]pyrans was obtained by suitable chemical methods. Pharmacological screening of these compounds showed the lack of psychotropic activity of the corresponding 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans.

Animals↗
PubMed1979

Studies on in vivo priming of the TNP-reactive cytotoxic effector cell system. I. Comparison of the effects of intravenous inoculation with TNP-conjugated cells on the development of contact sensitivity and cell-mediated lympholysis.

A comparison was made of the effects of i.v. inoculation of trinitrophenyl-(TNP) conjugated syngeneic cells on the subsequent in vitro generation of TNP-reactive effector cell activity and on the in vivo development of TNP-contact sensitivity. The administration of syngeneic TNP-conjugated spleen cells before 2,4,6-trinitro-1-chlorobenzene (TNCB) painting abolished the capability of animals to develop TNP-contact sensitivity. In contrast, the same treatment resulted in an appreciable augmentation in the generation of TNP-reactive cytotoxic effector cell activity as measured by subsequent in vitro sensitization with TNP-conjugated cells. The possible mechanisms by which enhanced TNP-reactive cytotoxic effector cell activity was elicited under conditions identical to those that induced unresponsiveness for TNP-contact sensitivity are discussed.

Animals↗
PubMed1975

[On the role of pentachlorocyclohexene in the metabolism and action of hexachlorocyclohexane. I. Synthesis of beta-pentachlorocyclohexene and its identification as the monodehydrochlorination product of alpha-hexachlorocyclohexane (author's transl)].

It is the aim of a series of investigations to test whether or not beta-pentachloro-1-cyclohexene is an intermediate in the biodegradation of alpha-hexachlorocyclohexane. This paper describes attempts to synthesize this intermediate by chemical methods. 1) Pentachlorocyclohexene was synthesized by partial additive chlorination of chlorobenzene. Combined gas chromatography-mass spectrometry revealed that at least five different isomers of pentachlorocyclohexene had been formed. 2) Treatment of alpha-hexachlorocyclohexane with alkaline buffer (pH 8) produced trichlorobenzenes and, in small yield (4%), a pentachlorocyclohexene. This was isolated and identified as the beta-isomer by melting point (71.8 - 72.6 degrees C, uncorr.), IR- and mass spectrum. Dehydrochlorination of beta-pentachlorocyclohexene produced the trichlorobenzene isomers in a pattern which is characteristic of alpha-hexachlorocyclohexane. The position of the chlorine substituents in the beta-pentachlorocyclohexene molecule as judged from NMR studies is e-aeee. This confirms that it is the monodehydrochlorination product of alpha-hexachlorocyclohexane. The configurations of gamma- and delta-pentachlorocyclohexene, determined for comparison, are e-eeaa and e-eeee, respectively. The kinetics of dehydrochlorination of both alpha-hexachlorocyclohexane and beta-pentachlorocyclohexene in alkaline acetone/water (3 + 2) was studied by means of conductometry. Both reactions are of second order: kappa alpha-HCH 0.0495 [1 times mol- minus 1 times s- minus 1[; kappa beta-PCH 0.905 [1 times mol- minus 1 times s- minus 1] (3.6 degrees C). 3) Dehydrochlorination of alpha-hexachlorocyclohexane in pyridine/xylene (3 + 4) was also studied. An earlier report claiming that gamma-pentachlorocyclohexene (and not the beta isomer) is produced in this medium was confirmed, if the reaction was performed at high temperature (120 - 140 degrees C). Moreover, the ratio of trichlorobenzene isomers formed from alpha-hexachlorocyclohexane shifted to a pattern characteristic of the gamma (or gamma) isomer. However, at temperatures of 90 degrees C or less, beta-pentachlorocyclohexene was the main product. The results strongly suggest that in pyridine/xylene, the same isomer is primarily produced from alpha-hexachlorocyclohexane and is isomerized to the gamma, delta and at least two other isomers of pentachlorocyclohexene before further dehydrochlorination ensues. A simple method for the synthesis of beta-pentachlorocyclohexene is presented.

Biodegradation, Environmental↗
PubMed1978

[Purification and properties of two chloridazondihydrodiol dehydrogenases from chloridazon degrading bacteria].

A cell-free extract of Chloridazon-degrading soil bacteria catalyzes the conversion of the dihydrodiol derivative of chloridazon to the corresponding catechol derivative. NAD is required as hydrogen acceptor. Chromatography of the crude extract on DEAE-cellulose results in the elution of two different enzymes (enzyme A and enzyme B, respectively) with the same catalytic capacity. Both enzymes were purified to homogeneity in disc-gel electrophoresis and their properties were compared. The molecular weight was found to be 220 000 for both enzymes. Dodecyl sulphate polyacrylamide gel electrophoresis indicated subunits of molecular weight 50 000 in both cases. The synthesis of the enzymes does not seem to be under inductive control. The two dehydrogenases differ in heat-stability, pH-optimum, Km-values for the substrate and in their sensitivity to inhibitors. Enzyme A shows relatively high heat lability, a pH-optimum at pH 9.5, and a Km-value of 0.25 mM for the dihydrodiol derivative of chloridazon. The catalytic activity of enzyme A is not influenced by p-chloromercuribenzoate or by N-bromosuccinimide. In contrast enzyme B is relatively stable at high temperatures, showing a pH-optimum of 7.0, and a Km for the dihydrodiol derivative of chloridazon of 1.0 mM. Enzyme B can be completely inhibited by even small amounts of p-chloromercuribenzoate and by N-bromosuccinimide. Striking differences were found in the substrate specificities of the two dehydrogenases. Whereas enzyme A exhibits a high specificity towards dihydrodiols derived from aromates of the chloridazon or phenazon type, enzyme B is much less specific and is also able to convert the dihydrodiols of benzene, toluene or chlorobenzene into the corresponding catechols. Both enzymes are competitively inhibited by the reaction product, the catechol of chloridazon. Other catechols differed in their inhibitory effect on the two dehydrogenases. These differences are correlated with the different substrate specificities.

Bacteria↗
PubMed1977

Pharmacokinetics: selectivity of action related to physicochemical properties and kinetic patterns of anticancer drugs.

Since the therapeutic index of drugs used for the treatment of cancer is small, optimal use depends on whatever advantage can be gained by achieving an effective concentration at the critical site in the cancer cell for a period of time sufficient to kill that cell while minimizing the action on normal cells or allowing their recovery. Advances in 1) methodology for measurement of minute amounts of drugs in tissues and body fluids, 2) better understanding of cell cycle kinetics and 3) development of kinetic models and computer simulation of compartmental drug distribution now aid better choice of dosage, mode of administration and treatment schedules. Limitations on the entry of amethopterin (Methotrexate) into cells and body compartments is compared with another folate antagonist, metroprine (DDMP), having the same mode of action, yet able to penetrate into brain. CSF and amethopterin-resistant cells because of greater lipid solubility. Pharmacokinetic considerations related to the limited effectiveness of present drugs for the treatment of brain tumors lead to the concept of "compartmental chemotherapy" based on selective drug contact with tumor combined with selective protection of tissues of limiting toxicity.

Animals↗
PubMed1979

Methane-oxygen enhanced negative ion mass spectra of polychlorinated diphenyl ethers.

Methane-oxygen enhanced negative ion mass spectra of 15 chlorinated diphenyl ethers contained some combination of [M-]-., [M-1]-, [M-19]-, [M-36]-, [M-55]-, and [M+35]- anions. The relative abundances of these ions are related to the chlorine substitution pattern. Similar ions appear in the negative ion spectra of polychlorinated anisoles. The study of known isomers of polychlorinated model compounds extends the utility of the negative ion method in the analysis of polychlorinated aromatics such as polychlorinated biphenyls, dioxins and furans. The spectra were shown to be very dependent on the temperature of the ion source; a temperature change of 25 degrees C was shown to have pronounced effects. Spectral variation with temperature has implications for computer library searches, ultimate sensitivity limits and analysis in the presence of interfering isobaric ions.

Chlorobenzenes↗
PubMed1975

Comparison of the hypnotic activity of triazolam, flurazepam hydrochloride, and placebo.

Triazolam, 0.4 and 0.8 mg, flurazepam, 15 and 30 mg, and placebo were compared in a double-blind, randomized 5-night crossover study in 25 inpatient insomniacs. These patients all complained difficulty falling asleep; all said they usually slept less than 5 hr a nigh and woke up too early in the morning. Results of the patients' global evaluation of the medications shows that all of the treatments were rated significantly higher than placebo, with the exception of triazolam, 0.4 mg, which was not significantly different from flurazepam, 15 or 30 mg, or from placebo. In subjective evaluation of sleep onset, only triazolam, 0.4 and 0.8 mg, was rated faster than placebo. All 4 active medications increased duration of sleep. Triazolam, 0.8 mg, and flurazepam, 30 mg, were rated as providing deeper sleep than placebo while all treatments except flurazepam, 15 mg, decreased the number of awakenings below that on placebo. A significant dose-response curve was obtained with triazolam and flurazepam for some of the parameters. Very few adverse effects were reported. One patient reported feeling groggy and drowsy on 0.4 mg triazolam while 2 reported nightmares on placebo.

Adult↗
PubMed1975

[Identification of metabolites and metabolism of hexachlorobenzene in a mold culture].

Hexachlorobenzene is but slowly metabolized by a lindane-decomposing mould culture, only pentachlorobenzene being detected as a metabolite. The degradation of pentachlorobenzene yields the following metabolites: pentachlorophenol, 2,3,4,5-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, 1,2,3,4-tetrachlorobenzene, 1,2,4,5- and/or 1,2,3,5-tetrachlorobenzene, 2,3,4-trichlorophenol, 2,4,6-trichlorophenol, 3,4,5-trichlorophenol, 1,3,5-trichlorobenzene. The establishment of a degradation pattern is under way.

Chlorine↗