Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The kinetics of micronucleus (MN) induction and decline in blood normochromatic erythrocytes (NCE) of mice subchronically exposed to benzene was investigated during and after exposure. Swiss (ICR) male mice (10/group) were given 0.0, 36.6, 73.2, and 146.4 mg/kg body weight benzene by gavage daily for 14 days, except for days 5 and 10. The frequency of MN increased significantly (P less than .001) during benzene treatment as a function of both concentration and time. Eleven days after exposure the levels of MN were higher than those observed at the end of exposure. After an initial rapid decline in the frequency of MN from 11 to 18 days postexposure, the decline became linear with time through 60 days postexposure. Using linear regression analysis, the MN level in each treatment group was predicted to reach control levels by approximately 85 days post-treatment. Dose-dependent suppression and recovery of erythropoiesis, estimated by polychromatic erythrocyte frequency, were observed in the 1st and 2nd weeks of exposure, respectively. Red blood cell (RBC) production was markedly increased in the first 3 weeks after benzene treatment. At later times the rate of production of the RBC returned to normal and may account for the linear decline observed in MN frequency. This research indicates that the frequency of MN is dose and duration dependent, while the decline in MN frequency after the end of benzene exposure can be related to changes in the kinetics of erythropoiesis.
Environ Mol Mutagen 1988
PMID:Persistence of micronuclei in peripheral blood normochromatic erythrocytes of subchronically benzene-treated male mice. 316 10

Simple energy calculations show that there is a significant interaction between a hydrogen bond donor (like the greater than NH group) and the centre of a benzene ring, which acts as a hydrogen bond acceptor. This interaction, which is about half as strong as a normal hydrogen bond, contributes approximately 3 kcal/mol (1 cal = 4.184 J) of stabilizing enthalpy and is expected to play a significant role in molecular associations. It is of interest that the aromatic hydrogen bond arises from small partial charges centred on the ring carbon and hydrogen atoms: there is no need to consider delocalized electrons. Although some energy calculations have included such partial charges, their role in forming such a strong interaction was not appreciated until after aromatic hydrogen bonds had been observed in protein-drug complexes.
J Mol Biol 1988 Jun 20
PMID:Aromatic rings act as hydrogen bond acceptors. 317 2

The ability of diethyl ether to serve as a substrate for microsomal and purified cytochrome P-450 (P-450) and as an inducer for rat hepatic microsomal monooxygenase activities was examined. Microsomal oxidation of ether to acetaldehyde, as monitored by high pressure liquid chromatography, was elevated 3- to 5-fold by treatment of rats with acetone or ethanol, 1.5- to 2-fold by treatment with ether, and only slightly by phenobarbital treatment. Ether also induced N-nitrosodimethylamine demethylase by up to 2-fold and 7-pentoxyresorufin dealkylation by up to 10-fold. These trends agreed with immunoblot experiments in which ether was a weak inducer of the P-450 isozyme IIE1 (encoded by the rat gene P450IIE1), but a stronger inducer of IIB1. A monoclonal antibody against IIE1 inhibited the deethylation by 78% in microsomes from acetone-treated rats and by 45% in controls. N-Nitrosodimethylamine, as well as common inhibitors of IIE1 such as hexane, benzene, pyrazole, and phenylethylamine, strongly inhibited ether deethylation. Using microsomes from acetone-induced rats, the apparent Km for deethylation was 13.4 +/- 2.4 microM and the Vmax was 8.2 +/- 0.2 (nmol of acetaldehyde/min/nmol of P-450). The Km for the controls was 71.3 +/- 9.5 microM. The rates of deethylation at 1 mM ether by purified, reconstituted IIE1 and IIB1 were 4.2 and 0.42 (nmol of acetaldehyde/min/nmol of P-450), respectively. Cytochrome b5 stimulated the rate due to IIE1 apparently by a decrease in the Km. These findings, along with previous work showing marked inhibition by ether of IIE1-dependent reactions, strongly support a major role for this isozyme in ether metabolism.
Mol Pharmacol 1988 Feb
PMID:Diethyl ether as a substrate for acetone/ethanol-inducible cytochrome P-450 and as an inducer for cytochrome(s) P-450. 334 79

Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269-278, 1975) and Clive et al. (Mutat Res 59:61-108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
Environ Mol Mutagen 1988
PMID:Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. 338 42

Combretastatin, an antineoplastic and antimitotic agent, was isolated from the bark of Combretum caffrum [Can. J. Chem. 60: 1374-1376 (1982); Biochem. Pharmacol. 32:3864-3867 (1983)]. Structurally, combretastatin consists of two substituted benzene rings linked by a saturated, hydroxy-substituted two-carbon bridge. A large number of combretastatin analogs have now been synthesized or obtained from C. caffrum. These vary in substituents on the phenyl rings or bridge carbons, bridge length, unsaturation of the bridge (i.e., stilbene derivatives, with the two phenyl rings oriented either cis or trans), and in precise ring structure (two major variants, with the bridge incorporated into a third six-member ring to form a phenanthrene structure or a methyl group eliminated from vicinal methoxy substituents to form a benzodioxole ring). Available analogs (17 natural products and 22 synthetic agents) were examined for antimitotic and cytotoxic activity and for effects on tubulin polymerization and colchicine binding. Nineteen compounds inhibited cell growth by 50% or more at concentrations of 1 microM or less, and 14 inhibited tubulin polymerization by at least 50% at stoichiometric drug concentrations. The most potent cytotoxic agents generally strongly inhibited both tubulin polymerization and the binding of colchicine to tubulin. The most promising compound is the (cis)-stilbene derivative (cis)-1-(3,4,5-trimethoxyphenyl)-2-(3'-hydroxy-4'-methoxyphenyl)ethene, which has been named combretastatin A-4. This compound inhibited cell growth by 50% at 7 nM, inhibited tubulin polymerization by 50% at 2.5 microM (1/4 molar equivalent), and competitively inhibited colchicine binding with an apparent Ki of 0.14 microM.
Mol Pharmacol 1988 Aug
PMID:Interactions of tubulin with potent natural and synthetic analogs of the antimitotic agent combretastatin: a structure-activity study. 341 21

The hydrophobicity of the peptide C=O ... H-N hydrogen-bonded group is an important parameter that determines the structure of proteins in water and in biological membranes, and therefore the free energy of transferring this group from water to non-polar solvents should be determined accurately. The essential work on this problem was carried out by Klotz and co-workers, and has been summarized elsewhere. Using N-methylacetamide as a model peptide, the free energies of the following processes were determined; (1) formation of the C=O ... H-N bond in water, (2) formation of the C=O ... N-N bond in CCl4, and (3) transfer of N-methylacetamide from water to CCl4. (4) From (3), the free energy of transferring the non-hydrogen bonded (C=O, H-N) group from water to CCl4 was calculated. When the free energies of (1), (2) and (4) are combined, one finds that the free energy of transferring the C=O ... H-N group from water to CCl4 is a surprising -1.4 kcal/mol (1 cal = 4.184 J). This number does not seem reasonable, since it implies that the C=O ... H-N group is about as hydrophobic as an isopropyl group, i.e. the side-chain of valine. In the present report, it is shown that this apparent hydrophobicity results from an underestimation of the free energy contribution that the methyl groups make to the transfer of N-methylacetamide from water to CCl4. When appropriate methyl group transfer free energies are used, one finds that the free energy of transferring the C=O ... H-N group from water to CCl4 is +0.62 kcal/mol. Therefore, this group is relatively insensitive to solvent polarity. A similar calculation shows that the free energy of transferring the C=O ... H-O hydrogen-bonded group from water to benzene is +0.55 kcal/mol.
J Mol Biol 1988 Jun 05
PMID:Hydrophobicity of the peptide C=O...H-N hydrogen-bonded group. 341 13

Acinetobacter calcoaceticus RJE74 contains a large transmissible catabolic plasmid, pWW174, of about 200 kb, which encodes its ability to grow on benzene (Bzn+). pWW174 was unstable in Acinetobacter hosts and was lost at high frequency in the absence of selection for Bzn+. The catabolic pathway appeared to be via benzene cis-glycol, catechol and the beta-ketoadipate (ortho) pathway. pWW174 encodes a catechol 1,2-oxygenase which is significantly more thermolabile than the chromosomally determined enzyme. pWW174 was able to complement all cat mutants (catechol to central metabolites) of A. calcoaceticus ADP1 (BD413) tested. Two regions of the plasmid were cloned, one carrying catA, the gene for catechol 1,2-oxygenase, and another carrying catBCDE, the subsequent four enzymes of the beta-ketoadipate pathway: these two regions appeared to be separated by at least 10 kbp. Hybridization indicated homology between the plasmid cat genes and the corresponding chromosomal genes of ADP1.
Mol Microbiol 1987 Sep
PMID:pWW174: a large plasmid from Acinetobacter calcoaceticus encoding benzene catabolism by the beta-ketoadipate pathway. 344 41

Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene-induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part to altered differentiation of marrow lymphoid cells. We investigated the effect of acute exposure to the benzene metabolite, hydroquinone, on murine bone marrow B-lymphopoiesis. Bone marrow cell suspensions from B6C3F1 (C57BL/6J x C3H/HeJ) mice were depleted of mature surface IgM+ (sIgM+) B cells and cultured for 0, 24, 48, or 72 hr and production of newly formed B cells was assayed both by sIgM expression and colony formation in soft agar cultures. One hr exposure of bone marrow cells to hydroquinone before culture reduced the number of sIgM+ cells generated in liquid cultures. Small pre-B cells (cytoplasmic mu heavy chain+, sIgM-) were numerically elevated as compared with control cultures. Hydroquinone exposure also decreased the number of adherent cells found in cultures of bone marrow cells. These results suggest that short-term exposure to hydroquinone, an oxidative metabolite of benzene, may in some way block the final maturation stages of B cell differentiation. This apparent differentiation block resulted in reduced numbers of B cells generated in culture and a corresponding accumulation of pre-B cells. Reduction of adherent cells in treated cultures may also suggest that toxicity to regulatory cells for the B lineage may be in part responsible for this aspect of hydroquinone myelotoxicity.
Mol Pharmacol 1987 Dec
PMID:Hydroquinone inhibits bone marrow pre-B cell maturation in vitro. 350 Oct 69

Two mouse X sheep interspecific cell hybrids were obtained by fusing mouse myeloma cell line Sp2/O. Ag14 with sheep lymphocytes obtained from a lymph node antigenically stimulated with azo-benzene arsonate-ovalbumin (ABA-ova). The interspecific cell lines were characterized using immunochemical, karyotypic and molecular DNA techniques. Both cell lines secreted sheep IgG1 antibody specific for the ABA haptenic determinant. Karyotypic analysis revealed that cell lines 4.11 and 11.9 had modal chromosome numbers of 91 and 106, respectively. Although C-banded spreads confirmed that fusion between sheep and mouse cells had occurred, it was not possible to differentiate sheep from mouse chromosomes. However, DNA hybridization techniques showed that each line contained sheep repetitive sequence DNA. It was calculated that cell line 11.9 contained 17640 copies while cell line 4.11 contained 734 copies of the previously characterized sheep satellite DNA.
Mol Immunol 1986 Jul
PMID:Characterization of two mouse myeloma X sheep lymphocyte cell lines secreting sheep antibody. 354 Jun 17

Synthetic nonsteroidal antiestrogens are bound intracellularly by two high affinity saturable bindings sites, the estrogen receptor and the microsomal antiestrogen-binding site (AEBS). In order to further define the structural requirements for ligand binding to AEBS from rat liver and the MCF 7 human breast cancer cell line, the relative binding affinities of an extensive series of structurally related ligands were investigated using competitive binding assay techniques. The groups of compounds studied were: analogues of the triphenylethylene antiestrogens, Cl 628 and tamoxifen; analogues of cyclofenil; bibenzyl and stilbene derivatives; analogues of the cytochrome P-450 inhibitor SKF-525A; phenothiazine derivatives; and a series of structurally related compounds with a variety of pharmacological activities. High affinity binding to AEBS required the presence of both a hydrophilic basic aminoether side chain and a hydrophobic aromatic ring structure (di- or tricyclic for maximal affinity). Structural modifications to either influenced binding affinity. Aromatic substitution either raised (CF3) or lowered (OH, OCH3) affinity, apparently by electronic effects transmitted through the benzene nucleus. Side chain structure was the major determinant of binding affinity, but its influence was complex and dependent upon terminal amino group structure, side chain branching and substitution, and tissue source of AEBS. Optimal binding affinity was shown by side chains bearing basic heterocyclic amino terminal groups. Other cellular sites that are known to bind antiestrogens with relatively high affinity include calmodulin, cytochrome P-450, and histamine, dopamine, and muscarinic receptors. Binding studies using a variety of pharmacologically active and radiolabeled ligands selective for these sites, including those for dopamine D1 and D2 receptors ([3H]fluphenazine, [3H]flupenthixol, [3H]spiperone, and [3H]SCH 23390) and histamine H1 receptors ([3H]pyrilamine), demonstrated that several of these compounds interact with AEBS with high affinity. However, the ligand specificity and other binding properties of the AEBS as determined by competitive binding studies and Scatchard analysis show this site to be a molecular entity truly distinct from these other cellular binding sites.
Mol Pharmacol 1987 May
PMID:Studies on the ligand specificity and potential identity of microsomal antiestrogen-binding sites. 355 93


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