Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Water-phospholipid (dimyristoylphosphatidylcholine) interaction was analyzed in a water-in-oil(benzene) reversed micellar system using Fourier transform infrared spectroscopy, and the effects of inhalation anesthetics (halothane, enflurane, chloroform, and carbon tetrachloride) on the interaction were studied. The O-H stretching frequency, representing water, increased from 3369 cm-1 to a steady 3430 cm-1 when the water/phospholipid mole ratio exceeded 18. The value did not quite reach the frequency of free water of 3490 cm-1 at the water/phospholipid mole ratio of 30. The O-H bending frequency of water did not appear until the water/phospholipid mole ratio exceeded 9. The P=O stretching frequency in the polar head group of unhydrated dimyristoylphosphatidylcholine was 1262 cm-1 and decreased with the addition of water, reaching a steady value of 1238 cm-1 at the water/phospholipid mole ratio of 9. However, the (CH3)3N+ stretching of the choline head, as well as the C-H stretching of the hydrocarbon tail and the C=O stretching of the ester linkage, showed little change by the addition of water. The present results suggest that the primary hydration site of dimyristoylphosphatidylcholine is the phosphate moiety, and up to 18 water molecules are restricted at the polar head group. Apparently, the choline head has a minor role in the hydration of phospholipids despite the positive electrostatic charge. Among the water molecules interacting with the phospholipid head group, about 9 water molecules are strongly bound. The water content in the micelles correlated linearly with the ratio of the absorbance band area between O-H and C=O stretching. The addition of polar anesthetics (halothane, enflurane, and chloroform) increased the O-H stretching frequency and elevated the ratio of the absorbance band area between O-H and C=O stretching, implying that the anesthetics released the structured water molecules bound at the phospholipid-water interface. The anesthetics disrupted the hydrogen bond between the phosphate moiety of the phospholipid and water. Although apolar carbon tetrachloride also released bound water molecules, the magnitude was less than that of the polar anesthetics, as expected. The anesthetics did not affect the C-H stretching or C=O stretching bands, indicating that the disordering action upon the hydrocarbon core of phospholipid membranes is minimal at low water content. These results support our view that the primary site of action of inhalation anesthetics is the membrane-water interface, releasing bound water molecules.
Mol Pharmacol 1987 Jun
PMID:Fourier transform infrared studies on phospholipid hydration: phosphate-oriented hydrogen bonding and its attenuation by volatile anesthetics. 360 Jun 7

The hydroxylation of p-nitrophenol to 4-nitrocatechol was investigated using rabbit hepatic microsomes and six purified isozymes of cytochrome P-450. The microsomal activity was maximal at pH 6.8 and at 100 microM p-nitrophenol. At higher substrate concentrations inhibition was observed. At pH 6.8 and 100 microM p-nitrophenol, isozyme 3a exhibited the highest activity of the purified isozymes: 3.4-fold more active than isozyme 6, and 8-fold more active than isozymes 2 and 4. The isozyme 3a-catalyzed hydroxylation reaction was stimulated 2.4-fold by the addition of a 4:1 ratio of cytochrome b5/P-450. At optimal concentrations of cytochrome b5, isozyme 3a was 8- to 9-fold more active than isozymes 2 and 6 and 20-fold more active than isozyme 4. Under the same conditions, isozyme 3a-catalyzed butanol oxidation was inhibited 40%. Antibodies to isozyme 3a inhibited greater than 95% of the p-nitrophenol hydroxylase activity of microsomes from untreated or from ethanol- or acetone-treated rabbits. The microsomal hydroxylase activity was linearly correlated with the microsomal concentration of isozyme 3a (correlation coefficient of 0.94) and had an intercept near zero. The results from reconstitution, antibody inhibition, and correlation experiments indicate that isozyme 3a is the principal catalyst of rabbit microsomal p-nitrophenol hydroxylation. The ability of the ethanol-inducible isozyme to catalyze catechol formation may be important in the ethanol-enhanced toxicity of aromatic compounds such as benzene.
Mol Pharmacol 1986 Apr
PMID:Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P-450 isozyme 3a. 370 59

A dimyristoylphosphatidylcholine multilamellar system with varied water content was prepared by dessiccating sonicated vesicles in vacuo. The water content in the sample was determined by gas chromatography after dissolving the multilamellar system in water-free benzene. Differential scanning microcalorimetry revealed several endothermic peaks in the heating scan at subzero temperature, ranging from -25 to -3 degrees. The peaks that appeared in the subzero temperature range indicate the existence of water molecules bound to the lipid head groups, differing from free water that freezes at 0 degrees. The difference between the amount of water molecules that froze in calorimetry and the total amount of water detected by gas chromatography indicates the presence of unfreezable, tightly bound water molecules. The relative amount of free, intermediate, and unfreezable water was estimated by comparing the differential scanning microcalorimetry data with gas chromatography measurements. The addition of halothane and 1-hexanol significantly decreased the intermediately bound water peaks. The anesthetics dehydrated the lamellar system. The phase polymorphism of partially hydrated phospholipid multilayers is well known, and the temperature that corresponds to the main phase transition of fully hydrated lipid membranes shifts to a higher temperature. The addition of anesthetics increased the phase transition temperature when the water content was less than 18 wt%. This result is the complete reverse of the depressant action of anesthetics in fully hydrated lipid membranes. The present anesthetic effect upon the elevation of the transition temperature is apparently caused by anesthetic-induced dehydration of the lipid-water interface at the present experimental condition.
Mol Pharmacol 1986 Jun
PMID:Anesthetics release unfreezable and bound water in partially hydrated phospholipid lamellar systems and elevate phase transition temperature. 371 2

Because DNA modification may be a prerequisite for chemical carcinogenesis, the DNA-damaging potential of benzene and its metabolites was examined in order to identify the proximate DNA-damaging agent associated with benzene exposure. A DNA synthesis inhibition assay previously identified p-benzoquinone as the most potent overall cellular toxin and inhibitor of DNA synthesis, but failed to discriminate among the hydroxylated metabolites. Therefore, the ability of benzene and its metabolites to induce DNA strand breaks in the mouse lymphoma cell line, L5178YS, was examined in order to provide a more accurate indication of the DNA damage associated with benzene and its metabolites. Cells were exposed to benzene, hydroquinone, catechol, phenol, 1,2,4-benzenetriol, or p-benzoquinone over a 1000-fold concentration range (1.0 microM-1.0 mM). Concentrations of benzene, phenol, or catechol as high as 1.0 mM did not increase the percentage of single-stranded DNA observed. Concentrations of hydroquinone as high as 0.1 mM were also ineffective. In contrast, both p-benzoquinone and 1,2,4-benzenetriol produced DNA breaks in a dose-related fashion. Of the two, benzoquinone proved to be more potent with an ED50 of approximately equal to 2.5 microM compared with 55.0 microM for benzenetriol. The DNA damage induced by 6.0 microM benzoquinone was maximal within 3 min of exposure and yielded approximately 70% single-stranded DNA after alkaline denaturation. By contrast, the single-stranded DNA observed after benzenetriol exposure required 60 min of exposure to achieve the same extent of damage as that found with benzoquinone. These results suggest that the benzene metabolites, benzenetriol and benzoquinone, may cause DNA damage and that the mechanisms responsible for the damage associated with these two compounds may be different.
Mol Pharmacol 1986 Jul
PMID:DNA damage in L5178YS cells following exposure to benzene metabolites. 372 44

The mechanism of microsomal hydroxylation of benzene to phenol has been studied by examining the microsomal metabolism of the specifically deuterated derivative 1,3,5-[2H3]benzene. Evidence for the formation of the following four products was obtained: 2,3,5-[2H3]phenol, 3,5-[2H2]phenol, 2,4,6-[2H3]phenol, and 2,4-[2H2]phenol. The presence of 2,3,5-[2H3]phenol and 2,4-[2H2]phenol shows that, in the microsomal metabolism of benzene to phenol, a NIH shift had occurred. A deuterium isotope effect (kH/kD) of approximately 4 was detected in both the meta- and para-deuterated phenols. This finding indicates that cyclohexadienone, formed either by isomerization of the epoxide or directly from the enzyme-substrate complex, is a major intermediate in the metabolism of benzene to phenol.
Mol Pharmacol 1985 May
PMID:Mechanism of microsomal metabolism of benzene to phenol. 399 Jun 79

1,4-bis-[2-(3,5-Dichloropyridyloxy)]-benzene (TCPOBOP) was previously shown to be an extremely potent phenobarbital-like inducer of hepatic microsomal monooxygenase activity in the mouse. To examine the structure-activity relationship, 31 congeners of TCPOBOP were synthesized and tested for their potency to induce hepatic aminopyrine N-demethylase activity in B6D2F1/J mice. For biological activity, the minimum requirement is a) a central 1,4-dioxygenated benzene ring, b) lateral pyridine rings linked to the central ring by ether bonds, but with other lateral heteroaromatic rings, e.g., quinoline or pyrimidine, also active, c) 5,5'-substituents of Cl, Br, or NO2 on the pyridine rings. For a series of 5,5'-substituted and 3,3'-dichloro,5,5'-substituted bispyridyloxybenzenes, no correlation was observed for Hansch pi and sigma p values. To account for this lack of correlation and conformational variability produced by the two ether bonds, we performed x-ray structure determinations on three compounds: a) TCPOBOP, b) the 5,5'-dichloro analogue, and c) the biologically inactive, 3,3'-dichloro analogue. In the two biologically active congeners the positioning of the pyridine rings is anti to the plane of the central benzene ring, and the dihedral angle between the central ring and the pyridines is approximately 60 degrees. In the inactive analogue the pyridine rings are syn and the dihedral angle is 84 degrees. The x-ray crystallographic data are consistent with the ether oxygen having an sp2-bonding conjugating with the heterodipolar bond of the pyridine C(2)--N(1), which strongly restricts rotation about the ether bonds. The potency of TCPOBOP and other bispyridyloxybenzene analogues to induce a phenobarbital-like pleiotropic response and the sharply defined structure-activity relationship among these congeners support the hypothesis that they act by binding to a specific recognition site.
Mol Pharmacol 1985 Nov
PMID:Structure-activity relationship of bispyridyloxybenzene for induction of mouse hepatic aminopyrine N-demethylase activity. Chemical, biological, and X-ray crystallographic studies. 405 24

The effects of benzene and its metabolites on the rate of DNA synthesis were measured in the mouse lymphoma cell line, L5178YS. The direct toxicity of benzene could be distinguished from that of its metabolites since bioactivation of benzene in L5178YS cells was not observed. Cells were exposed to benzene, phenol, catechol, hydroquinone, p-benzoquinone, or 1,2,4-benzenetriol over the range of 1.0 X 10(-7) to 1.0 X 10(-2) M for 30 min, and the rate of DNA synthesis was measured at various times after chemical washout. Cell viability and protein synthesis were determined by trypan blue dye exclusion and [3H]leucine incorporation, respectively. Effects were designated as "DNA specific" when DNA synthesis was inhibited in the absence of discernible effects on cell membrane integrity and protein synthesis. Concentrations of benzene as high as 1 mM had no effect on DNA synthesis. Comparison of the effects at the maximum nontoxic dose for each compound showed that catechol and hydroquinone were the most effective, inhibiting DNA synthesis by 65%. Phenol, benzoquinone, and benzenetriol inhibited DNA synthesis by approximately 40%. Maximum inhibition was observed 60 min after metabolite washout in each case. Benzoquinone was the most potent inhibitor of DNA synthesis, followed by hydroquinone, benzenetriol, catechol, and phenol with ED50 values of 5 X 10(-6), 1 X 10(-5), 1.8 X 10(-4), 2.5 X 10(-4), and 8.0 X 10(-4), respectively. Cyclic voltammetric experiments were performed on the hydroxylated metabolites of benzene to assess the possible involvement of a redox-type mechanism in their inhibition of DNA synthesis. The ease of oxidation of these metabolites correlated with their ED50 values for inhibition of DNA synthesis (r = 0.997). This suggests that oxidation of phenol or one of its metabolites may be necessary for production of the species involved in inhibition of DNA synthesis.
Mol Pharmacol 1985 Dec
PMID:Relationship between the oxidation potential of benzene metabolites and their inhibitory effect on DNA synthesis in L5178YS cells. 407 12

We propose that the conformation of 1,4-benzodiazepines that is recognized by the binding site on the benzodiazepine receptor complex is one in which the planes formed by the fused benzene ring and the methylene group (and the two adjoining atoms) of the diazepine ring are in the R configuration. The derivation of this conformation was based on comparisons of computer-generated 3-dimensional structures obtained from single-crystal X-ray data for diazepam, (R)- and (S)-1,3-dimethyl-5-(2-fluorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2- one, and the structurally rigid ethyl (S)-7-chloro-11,12,13,13 alpha-tetrahydro-9-oxo-9H-imidazo[1,5-alpha] pyrrolo[2,1-d][1,4]benzodiazepine-1-carboxylate. The affinity of ligands for the benzodiazepine binding site was determined using the [3H]-diazepam binding assay.
Mol Pharmacol 1983 Nov
PMID:Quinazolines and 1,4-benzodiazepines. 92. Conformational recognition of the receptor by 1,4-benzodiazepines. 631 15

The role of various enzymes and biological molecules on the activation and deactivation of the metabolites of phenol was investigated in vitro. Phenol, the major metabolite of benzene, is metabolized to hydroquinone and catechol. Activation of these metabolites and deactivation of their oxidized forms was assessed by the amount of covalent binding to microsomal protein. [14C]Phenol and NADPH were incubated with hepatic microsomes isolated from phenobarbital-pretreated guinea pigs, and 2.33 nmoles of hydroquinone and 0.12 nmole of catechol were formed per minute per milligram of microsomal protein. Covalent binding of the metabolites to microsomal protein incubated with microsomes isolated from guinea pigs pretreated with phenobarbital was 252 pmoles bound/min/mg; with microsomes from untreated guinea pigs, covalent binding was 146 pmoles bound/min/mg. Covalent binding was inhibited greater than 90% with the addition of N-octylamine, ascorbate, or GSH. The addition of superoxide dismutase inhibited covalent binding with microsomes isolated from phenobarbital-pretreated guinea pigs 35% but did not inhibit it with microsomes isolated from untreated animals. Partially purified guinea pig hepatic DT-diaphorase [NAD(P)H (quinone acceptor) oxidoreductase, EC 1.6.99.2] inhibited covalent binding 70%. This effect was reversed in the presence of dicumarol, a specific inhibitor of DT-diaphorase. DT-diaphorase present in the 10(5) X g supernatant fraction was also active in inhibiting covalent binding but only after the removal of endogenous reduced glutathione. This effect could also be reversed by dicumarol. The addition of diaphorase (NADH:lipoamide oxidoreductase, EC 1.6.4.3) partially purified from Clostridium kluyveri inhibited covalent binding 86%. The addition of hydrogen peroxide and horseradish peroxidase (peroxidase, EC 1.11.17) or myeloperoxidase(s) increased covalent binding 30-fold and 6-fold, respectively. Ascorbate decreased this binding greater than 95%. These results indicate that hydroquinone, catechol, and phenol as well as their oxidized forms can be activated or deactivated by several of the above model systems. These systems may play a role in the myelotoxicity of benzene by modulating covalent binding.
Mol Pharmacol 1984 Jul
PMID:DT-diaphorase and peroxidase influence the covalent binding of the metabolites of phenol, the major metabolite of benzene. 674 27

Semiempirical molecular orbital calculations (by modified neglect of diatomic overlap method) were performed on diol epoxide metabolites of five polycyclic aromatic hydrocarbons (PAHs)--benzene, naphthalene, phenanthrene, chrysene, and benzo[a]pyrene (BP)--to gain insight into the various carcinogenic potencies of these compounds. Opening of the epoxide rings of the diol epoxides was calculated to be exothermic for all of the PAHs investigated. The bay-region diol epoxides of BP were calculated to open spontaneously to the triol carbonium ion upon protonation. For the bay-region trans- and cis-diequatorial diol epoxides of 5-methylchrysene the methyl group destabilized the epoxide. These results suggest that the conformation of the saturated, angular benzo-ring is important in determining bay-region epoxide stability. Conformational flexibility of the aromatic ring system is offered as one reason for partial stabilizing of bay-region epoxides. These results also suggest that the existence and potentiation of PAH carcinogenicity is correlated with the lack of stability of the bay-region epoxide ring. Considerations of thermochemical stability have value in predictions of carcinogenic potency.
Mol Pharmacol 1982 Sep
PMID:Molecular orbital studies of epoxide stability of carcinogenic polycyclic aromatic hydrocarbon diol epoxides. 714 38


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>