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PubMed1999

[Human exposure to trihalomethanes in drinking water].

Halogenated hydrocarbon compounds, some of them recognized as carcinogenic to different animal species can be found in drinking water. Chloroform, bromodichloromethane, dibromochloromethane and bromoform are the most important trihalomethanes found in potable water. They are produced in natural waters during chlorinated desinfection by the halogenation of precursors, specially humic and fulvic compounds. The review, in the MEDLINE covers the period from 1974 to 1998, presents the general aspects of the formation of trihalomethanes, sources of human exposure and their toxicological meaning for exposed organisms: toxicokinetic disposition and spectrum of toxic effects (carcinogenic, mutagenic and teratogenic).

Carcinogens↗
PubMed2006

Catalytic destruction of brominated aromatic compounds studied in a catalyst microbed coupled to gas chromatography/mass spectrometry.

The capability of solid porous catalysts has been studied for the destruction or modification of halogenated aromatic compounds contaminating the pyrolysis oil of recycled plastics from electronic waste. A fast and simple experimental procedure is carried out using a micropyrolyser coupled to GC-MS in such a way that catalyst microbed was placed in the sample tube of the pyrolyser. The pyrolysis products of polycarbonate blended with a frequently applied flame retardant tetrabromobisphenol A (TBBPA) and epoxy resin containing TBBPA monomer units have been analysed, and the brominated components were compared with the thermal decomposition products of TBBPA and its diallyl ether. When TBBPA vapour passes through molecular sieve 4A a slight debromination and a partial cleavage of bisphenol A into phenols occur. Over molecular sieves of larger pore size (13X and NaY zeolite) an important decrease of TBBPA amount is observed indicating effective trapping ability of these catalysts of basic character for brominated aromatic compounds. A total chemical modification of the vapour was achieved by Al-MCM-41 catalyst that split TBBPA into bromophenols. Analogous results were obtained by carrying out similar experiments on diallyl ether of TBBPA. Moreover, it was revealed that brominated bisphenol A compounds are modified essentially the same way, either evaporated or evolved from a polycarbonate blend or produced by pyrolysis from an epoxy resin.

Catalysis↗
PubMed1998

Methanotrophs, Methylosinus trichosporium OB3b, sMMO, and their application to bioremediation.

One of the most problematic groups of the USEPA and EU priority pollutants are the halogenated organic compounds. These substances have a wide range of industrial applications, such as solvents and cleaners. Inadequate disposal techniques and accidental spillages have led to their detection in soil, groundwater, and river sediments. Persistence of these compounds in the environment has resulted from low levels of biodegradation due to chemical structural features that preclude or retard biological attack. Research has indicated the idea that treatment systems based on methanotrophic co-metabolic transformation may be a cost-effective and efficient alternative to physical methods because of the potential for high transformation rates, the possibility of complete compound degradation without the formation of toxic metabolites, applicability to a broad spectrum of compounds, and the use of a widely available and inexpensive growth substrate. A substantial amount of work concerning methanotrophic cometabolic transformations has been carried out using the soluble form of methane monooxygenase (sMMO) from the obligate methanotroph Methylosinus trichosporium OB3b. This NADH-dependent monooxygenase is derepressed when cells are grown under copper stress. sMMO has a wider specificity than the particulate form. sMMO has been shown to degrade trichloroethylene (TCE) at a rate of at least one order of magnitude faster than obtained with other mixed and pure cultures, suggesting it has a wider application to bioremediation. Furthermore, sMMO catalyzes an unusually wide range of oxidation reactions, including the hydroxylation of alkanes, epoxidation of alkenes, ethers, halogenated methanes, cyclic and aromatic compounds including compounds, that are resistant to degradation in the environment. However, the practical application of methantrophs and Methylosinus trichosporium OB3b to the treatment of chlorinated organics has met with mixed success. Although oxidation rates are rapid, compound oxidation with M. trichosporium OB3b is difficult. This fastidious organism grows relatively slowly, which limits the speed with which sMMO expressing biomass can be generated. Furthermore, product toxicity toward the cell, affecting the stability of the enzyme when transforming certain compounds has been observed, for example, by the products of 1,2,3 trichlorobenzene hydroxylation (2,3,4- and 3,4,5-trichlorophenol) and of TCE degradation (chloral hydrate). Because of this toxicity and the inability of sMMO to further oxidize its own hydroxylation products, the ability of methane monoxygenase to carry out the monooxygenation of a wide variety of substituted aromatics and polyaromatics cannot be fully exploited in M. trichosporium OB3b. Many of these problems could be overcome by the use of either a mixed downstream heterotrophic population of organisms that could accommodate the products of hydroxylation or to express sMMO in an organism that could metabolize the products of hydroxylation. The latter of these two approaches would have several advantages. The main benefit would be the removal of the need for methane, which is required to induce sMMO in M. trichosporium OB3b, and supply carbon and energy to the cells that continuously oxidise the target compound, but also acts as a competitive inhibitor of sMMO. Instead, the recombinant could utilize the products of sMMO-mediated hydroxylation as a carbon source.

Biodegradation, Environmental↗
PubMed1997

[Theoretical rationale for structure-genotoxicity relationships in the series of halogenated short-chain aliphatic compounds for mammals and bacteria].

Structure-genotoxicity relationships for mammals and structure-mutagenic activity relationships for bacterial were derived in the series of halogenated short-chain hydrocarbons and alcohols, by using the calculated quantum chemical parameters, namely the energy differences of frontier molecular orbitals and the electronic characteristics of the probable metabolites.

Alcohols↗
PubMed1985

Chloracne and chloracnegens.

Chloracne, an acneform eruption resulting from poisoning by halogenated aromatic compounds, has been a considerable problem over the last 40 years. The condition is always a symptom of systemic poisoning and should be familiar to all practitioners, particularly dermatologists. It is difficult to treat and can last for long periods without known additional exposure to chloracnegens. Some chloracnegens are capable of causing a variety of systemic signs and symptoms and may be oncogenic. Although there are probably fewer than 4,000 persons with chloracne worldwide, those found with the disorder should be evaluated medically on a regular basis and followed, if possible, throughout their lives.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1986

Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides.

A series of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamides was synthesized, starting from the 2,6-dimethoxybenzoic acids, by boron tribromide demethylation of the corresponding 3,5-disubstituted 2,6-dimethoxybenzamides and separation of the two positional isomers. The correct structure assignments were based on selective decoupling studies on their 13C NMR spectra. The salicylamide derivatives were tested for antidopamine activity in vivo by their ability to inhibit the apomorphine syndrome in the rat and in vitro by their ability to displace [3H]spiperone from striatal preparations of the rat brain. The activity seems to reside exclusively in the S enantiomer. Several compounds were considerably more potent than haloperidol, particularly those having an ethyl group in the 3-position and a halogen atom in the 5-position of the aromatic ring. The corresponding 5-alkyl-3-halogen-substituted compounds were much less active. A low acute toxicity was found for the most potent compounds. Some of the salicylamides displayed a 10-20-fold separation between the dose which blocks apomorphine-induced hyperactivity and that which blocks apomorphine-induced stereotypy. One compound, S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-6-methoxysalicylamide (raclopride, FLA 870) (13) had a stereotypy--hyperactivity separation more than twice that of sulpiride while being 100 times more potent in blocking the apomorphine effects. On this basis, 13 was selected for clinical trials against schizophrenia.

Animals↗
PubMed1990

Synthesis, antiproliferative, and antiviral activity of certain 4-substituted and 4,5-disubstituted 7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3-d]pyrimidines.

The sodium salts of 4-chloro- and several 4-chloro-5-substituted-7H-pyrrolo[2,3-d]pyrimidines were treated with [1,3-bis(benzyloxy)-2-propoxy]methyl chloride (6) to provide the corresponding 4-chloro- and 4-chloro-5-substituted-7-[[1,3-bis(benzyloxy)-2-propoxy]methyl]pyrrolo [2,3-d]pyrimidines (7-11). Debenzylation with boron trichloride at -78 degrees C furnished 4-chloro- and several 4-chloro-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (12.16). Subsequent amination of 12-16 yielded the 4-amino-5-substituted-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrolo[2,3- d]pyrimidines (17-21). Treatment of 14 with methylamine and 13 and 14 with ethylamine yielded the 4-(alkylamino)-5-halo-7-[(1,3-dihydroxy-2- propoxy)methyl]pyrrolo[2,3-d]pyrimidines (22-24). Treatment of 12-15 with hydroxylamine in refluxing 2-propanol yielded the 5-substituted-4-(hydroxyamino)-7-[(1,3-dihydroxy-2-propoxy)methyl]pyrrol o [2,3-d]pyrimidines (25-28). Treatment of compound 12 with Pd/C under a hydrogen atmosphere has furnished the nebularine analogue 31. The antiproliferative activity of compounds 17-28 and 31 was studied using L1210 cells in vitro. The 4-amino- and 4-(hydroxyamino)-5-halogenated derivatives (compounds 18-20, 26-28) inhibited cell growth. Although the effect of compounds 18-20 and 27 on final growth rate was pronounced (IC50 = 2.3, 0.7, 2.8, and 3.7 microM, respectively), cells underwent at least one doubling before cell division stopped. The remaining compounds were less cytotoxic, with IC50's greater than 30 microM for 21, 23, 26, and 28, whereas no inhibition of L1210 cell growth was observed with compounds 17, 22, 24, 25, and 31 at 100 microM. The antiviral activity of these compounds also was tested. Compounds 18-20 and 26-28 were active against human cytomegalovirus and herpes simplex type 1. The 4-amino derivatives (18-20) were more active than the 4-hydroxyamino derivatives (26-28), the 4-amino-5-bromo and 4-amino-5-iodo derivatives produced more than five log reductions in virus titer at concentrations of 10-100 microM. Although some cytotoxicity was observed at these concentrations, compound 19 was active against murine cytomegalovirus in vivo. At 5.6 mg/kg, 14/15 animals survived compared to 10/15 treated with 5.6 mg/kg of ganciclovir or 1/15 treated with placebo.

Animals↗
PubMed2003

QSPR-based prediction of adsorption of halogenated aromatics on yellow-brown soil.

Halogenated aromatic compounds exist widely in soil and aqueous environment. The study of their transport and distribution is quite important for pollution control and risk assessment. In the present work the adsorption coefficients of 28 halogenated benzenes, anilines and phenols on yellow-brown soil were measured with batch equilibrium method, and a prediction model was developed through the quantitative structure-property relationship (QSPR) technique. Then the obtained model was tested with Monte Carlo simulation and Jacknife methods. The results indicated that it was robust enough to estimate soil adsorption behaviors for the tested compounds. Based on the obtained model it could be deduced that the adsorption of halogenated aromatics on yellow-brown soil was not a simple partitioning process but involved complicated interactions.

Adsorption↗
PubMed1984

Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential.

Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. Compounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 comprises of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamines form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemicals and Industrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity (the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the damage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to demonstrate one possible way for an experimental assessment and it is shown that the detoxification reaction at the methyl group available only in toluene gives rise to a reduction by at least a factor of forty for the binding to rat liver DNA. This quantitative approach available with DNA-binding tests in vivo, also allows evaluation as to whether reactive metabolites and their DNA binding are always the most important single activities contributing to the overall carcinogenicity of a chemical.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Rate constants for the reactions of halogenated organic radicals.

Absolute rate constants have been measured by means of pulse radiolysis for the reactions of various halogenated aliphatic compounds (ethane derivatives, including the anaesthetics halothane, enflurane, isoflurane and methoxyflurane) with hydrated electrons and .OH radicals, the reactions of halogenated carbon-centered radicals, derived thereby, with molecular oxygen, and the reactions of halogenated peroxyl radicals with various antioxidants (ascorbate, chlorpromazine, promethazine, propyl gallate, ABTS) in aqueous solutions. All oxygen addition reactions occur essentially diffusion-controlled. This finding is correlated with the stereoelectronic properties of the primary carbon-centred radicals. The oxidative power of the halogenated peroxyl radicals reflects the inductive -I effect of the halogens and accordingly increases with the degree of halogen substitution, with fluorine substituents being particularly effective. The peroxyl radicals derived from freon 113, namely CClF2CClFOO. and CCl2FCF2OO., have been identified as the best oxidants among these species.

Anesthetics↗
PubMed1983

Structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones. Metaphase arresting properties and competitive inhibition of colchicine binding to tubulin.

The structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones with respect to mitotic inhibitory potential and inhibition of colchicine binding to tubulin was investigated. A correlation between accumulation in metaphase of cultured human NHIK 3025 cells and drug competition with colchicine binding to tubulin was found for each compound. Effects on division of NHIK 3025 cells were determined in stained preparations following a 6 h treatment with drugs. The four halogen-substituted compounds displayed metaphase arresting ability while the H-substituted 1-propargylpyrimidin-2-one did not. 1-Propargyl-5-fluoropyrimidin-2-one was active at 1.5 and 0.75 mM while the 5-chloro, 5-bromo and 5-iodo compounds caused metaphase arrest at 0.375 and 0.18 mM. The ability of these drugs to compete with colchicine binding to DEAE-cellulose purified tubulin was also investigated. 1-Propargylpyrimidin-2-one at 5 mM did not inhibit (3H)colchicine binding to tubulin as determined by Sephadex G-50 gel filtration. The halogen-substituted pyrimidones, however, demonstrated competitive inhibition of colchicine binding to tubulin. Five mM 1-propargyl-5-iodopyrimidin-2-one inhibited colchicine binding by 43.2%, the highest value obtained within the metahalone group. The drugs tested had no effect on vincristine binding to tubulin. With respect to the halogen substitution, the increasing order of mitotic inhibitory potential and competition with colchicine binding to tubulin is H less than less than F less than Cl less than or equal to Br less than or equal to I.

Binding, Competitive↗
PubMed1999

Inhibition of select mitochondrial enzymes in PC12 cells exposed to S-(1,1,2,2-tetrafluoroethyl)-L-cysteine.

Many halogenated foreign compounds are detoxified by conversion to the corresponding cysteine S-conjugate, which is N-acetylated and excreted. However, several halogenated cysteine S-conjugates [e.g. S-(1,1,2,2-tetrafluoroethy)-L-cysteine (TFEC)] are converted to mitochondrial toxicants by cysteine S-conjugate beta-lyases. In the present work, we showed that TFEC appreciably inactivated highly purified alpha-ketoglutarate dehydrogenase complex (KGDHC) in the presence of a cysteine S-conjugate beta-lyase. Incubation of PC12 cells (which contain endogenous cysteine S-conjugate beta-lyase activity) with TFEC led to a concentration- and time-dependent loss of endogenous KGDHC activity. A 24-hr exposure to 1 mM TFEC decreased KGDHC activity in the cells by 90%. Although treatment with TFEC did not inhibit intrinsic pyruvate dehydrogenase complex (PDHC) activity, it inhibited dichloroacetate/Mg2+-mediated activation/dephosphorylation of PDHC in the PC12 cells by 90%. To determine the selectivity of enzymes targeted by TFEC, several cytosolic and mitochondrial enzymes involved in energy metabolism [malate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, glutamate dehydrogenase, lactate dehydrogenase, cytosolic and mitochondrial aspartate aminotransferases (AspAT)] were also assayed in the PC12 cells exposed to 1 mM TFEC for 24 hr. Of these enzymes, only mitochondrial AspAT, a key enzyme of the malate-aspartate shuttle, was inhibited. The present results demonstrate a selective vulnerability of mitochondrial enzymes to toxic cysteine S-conjugates. The data indicate that TFEC may be a useful cellular/mitochondrial toxicant for elucidating the consequences of the diminished mitochondrial function that accompanies numerous neurodegenerative diseases.

Animals↗
PubMed2003

Photocontact dermatitis and chloracne: two major occupational and environmental skin diseases induced by different actions of halogenated chemicals.

Among occupational and environmental disorders, contact or photocontact dermatitis and an acneiform eruption are two major skin disorders. Photocontact dermatitis was historically caused by various halogenated salicylanilides, while the acne is induced by halogenated aromatic hydrocarbons and thus called chloracne. Therefore, it should be noted that halogenated chemical compounds are important causative agents in the occupational and environmental medicine. In photocontact dermatitis, photoconjugation of epidermal cells with a photohaptenic halogenated chemical is the initial step. Langerhans cells serve as antigen-presenting cells and T cells sensitized by photoantigen-bearing Langerhans cells induce this photosensitivity. On the other hand, in chloracne, halogeneted hydrocarbons render keratinocytes of the outer root sheath and sebaceous duct hyperplastic. The dilated infundibulum of most hair follicles is then filled with comedone that consist of many accumulated layers of keratinized cells and sebum. Therefore, halogenated chemicals exhibit different actions, i.e. the induction of an immunologic consequence and the modulation of keratinocyte biology. These two conditions also provide good experimental models for investigating dermatology.

Acne Vulgaris↗
PubMed1996

Formation of Metal Clusters or Nitrogen-Bridged Adducts by Reaction of a Bis(amino)stannylene with Halides of Two-Valent Transition Metals.

When the cyclic bis(amino)stannylene Me(2)Si(NtBu)(2)Sn is allowed to react with metal halides MX(2) (M = Cr, Fe, Co, Zn; X = Cl, Br [Zn]) adducts of the general formula [Me(2)Si(NtBu)(2)Sn.MX(2)](n) are obtained. The compounds are generally dimeric (n = 2) except the ZnBr(2) adduct, which is monomeric in benzene. The crystal structures of [Me(2)Si(NtBu)(2)Sn.CoCl(2)](2) (triclinic, space group &Pmacr;1; a = 8.620(9) Å, b = 9.160(9) Å, c = 12.280(9) Å, alpha = 101.2(1) degrees, beta = 97.6(1) degrees, gamma = 105.9(1) degrees, Z = 1) and of [Me(2)Si(NtBu)(2)Sn.ZnCl(2)](2) (monoclinic, space group P2(1)/c; a = 8.156(9) Å, b = 16.835(12) Å, c = 13.206(9) Å, beta = 94.27(6) degrees, Z = 2) were determined by X-ray diffraction techniques. The two compounds form similar polycyclic, centrosymmetrical assemblies of metal atoms bridged by chlorine or nitrogen atoms. While in the case of the cobalt compound Co is pentacoordinated by three chlorine and two nitrogen atoms, in the zinc derivative Zn is almost tetrahedrally coordinated by three chlorine atoms and one nitrogen atom. The iron derivative [Me(2)Si(NtBu)(2)Sn.FeCl(2)](2) seems to be isostructural with the cobalt compound as can be deduced from the crystal data (triclinic, a = 8.622(7) Å, b = 9.158(8) Å, c = 12.353(8) Å, alpha = 101.8(1) degrees, beta = 96.9(1) degrees, gamma = 105.9(1) degrees, Z = 1). If NiBr(2), PdCl(2), or PtCl(2) is combined with the stannylene, the reaction product is totally different: 4 equiv of the stannylene are coordinating per metal halide, forming the molecular compound [Me(2)Si(NtBu)(2)Sn](4)MX(2), which crystallizes with half a mole of benzene per molecular formula. The crystal structures of [Me(2)Si(NtBu)(2)Sn](4).NiBr(2).(1)/(2)C(6)H(6) (tetragonal, space group I4(1)/a, a = b = 43.86(4) Å, c = 14.32(2) Å, Z = 16) and [Me(2)Si(NtBu)(2)Sn](4).PdCl(2).(1)/(2)C(6)H(6) (tetragonal, space group I4(1)/a, a = b = 43.99(4) Å, c = 14.318(14) Å, Z = 16) reveal the two compounds to be isostructural. The molecules have an inner Sn(4)M pentametallic core (mean distances: Sn-Ni 2.463 Å, Sn-Pd 2.544 Å) with the transition metal in the center of a slightly distorted square formed by the four tin atoms, the distortion from planarity resulting in a weak paramagnetism of 0.2 &mgr;(B) for the nickel compound. The halogen atoms form bridges between two of the tin atoms and have no bonding interaction with the transition metal. The nickel compound has also been prepared by direct interaction of Br(2) or NR(4)Br(3) with [Me(2)Si(NtBu)(2)Sn](4)Ni as a minor product, the main products being Me(2)Si(NtBu)(2)Sn(NtBu)(2)SiMe(2,) Me(2)Si(NtBu)(2)SnBr(2), NiBr(2) and SnBr(2). Other metal clusters have been obtained by the reaction of Me(2)Si(NtBu)(2)Sn with tetrakis(triphenyphosphine)palladium or by the reaction of Me(2)Si(NtBu)(2)Ge with RhCl(PPh(3))(3). In the first case Ph(3)PPd[Sn(NtBu)(2)SiMe(2)](3)PdPPh(3) (rhombohedral, space group R3c, a = b = 21.397(12) Å, c = 57.01(5) Å, alpha = beta = 90 degrees, gamma = 120 degrees, Z = 12) is formed and is characterized by X-ray techniques to be composed of a central PdSn(3)Pd trigonal bipyramid with the tin atoms occupying the equatorial positions (Pd-Sn = 2.702(5) Å). In the second reaction all the triphenylphosphine ligands are replaced from rhodium and Rh[Ge(NtBu)(2)SiMe(2)](4)Cl is formed (monoclinic, space group P2(1)/n, a = 12.164(2) Å, b = 23.625(5) Å, c = 24.128(5) Å, beta = 102.74(3) degrees, Z = 4). The central core of this molecule is made up of a rhodium atom which is almost square planarly coordinated by the germanium atoms, two of which are bridged by chlorine (mean Ge-Rh = 2.355 Å).

Journal Article↗
PubMed1986

Ethanol oxidation and toxicity: role of alcohol P-450 oxygenase.

The isolation and characterization of ethanol-inducible rabbit liver microsomal cytochrome P-450, termed P-450 3a or P-450ALC, has provided definitive evidence for the role of this enzyme in alcohol oxidation. From findings on the distribution, substrate specificity, and mechanism of action of P-450ALC we have suggested "alcohol P-450 oxygenase" as a more biochemically accurate name than "microsomal ethanol-oxidizing system." The present review is concerned with studies in this and other laboratories on activities and inducers associated with this versatile enzyme. Numerous xenobiotics, including alcohols and ketones, nitrosamines, aromatic compounds, and halogenated alkanes, alkenes, and ethers, are known to undergo increased microsomal metabolism after chronic exposure of various species to ethanol. Diverse compounds and treatments may induce P-450ALC, including the administration of ten or more chemically different compounds, fasting, or the diabetic state. Whether a common mechanism of induction is involved is unknown at this time. As direct evidence that P-450ALC catalyzes numerous metabolic reactions, the purified rabbit enzyme has been used in a reconstituted system to demonstrate various metabolic transformations, including the oxidation of various alcohols, acetone, acetol, p-nitrophenol, and aniline, the dealkylation of substituted nitrosamines, the reductive dechlorination of carbon tetrachloride, carbon tetrachloride-induced lipid peroxidation, and acetaminophen activation to form the glutathione conjugate.

Animals↗
PubMed1988

Synthesis and estrogen receptor selectivity of 1,1-bis(4-hydroxyphenyl)-2-(p-halophenyl)ethylenes.

A series of triarylethylenes (1a-e) were synthesized and evaluated for their ability to compete with [3H]estradiol for high-affinity estrogen receptors (ER) in immature rat uterine cytosol. All compounds showed affinity comparable to that of estradiol, with 1c having the highest affinity and the lowest calculated nonspecific binding of the para-halogenated members. Compound 1a had a higher affinity than did its chlorovinyl counterpart 1b, indicating that a vinyl hydrogen was suitable for high ER affinity in this series. Compound 1c was labeled with 3H ortho to one or both of its hydroxyls. Its ratio of specific to nonspecific binding in rat uterine cytosol, 3.2, was 140% of that of a related triarylethylene, 4-hydroxytamoxifen, and was 24% that of estradiol. Administration of [3H]-1c to immature female rats resulted in accumulation of 3H in uterine tissue which was decreased 39% when [3H]-1c was coadministered with estradiol. The major site of accumulation 1, 4, and 8 h after administration was in the intestinal tract. Chromatographic analysis showed that levels of 1c were less than those of 1c glucuronide in blood plasma, liver, and intestinal contents of rats 1 h after administration of 1c. Uterine 3H was comprised of 85% of 1c and 11% of 1c glucuronide. These results indicate that 1c undergoes ER-mediated uptake in the immature female rat, but selectivity is reduced due to nonspecific accumulation of free and conjugated 1c in uterine tissue.

Animals↗