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Query: UNIPROT:P06889 (Mol)
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The results of Molecular Orbital (MO) calculations by the MINDO/3 method are reported, together with the results of multiple regression analysis of electronic and structural parameters with inhibition of aniline hydroxylation by a series of 22 alcohols. The most significant correlations show the relationships between molecular length, frontier electron density of the alpha-carbon and hydroxyl oxygen, nucleophilic superdelocalizability of the hydroxyl hydrogen, energy of the highest occupied MO and biological activity involving binding to microsomal cytochromes P-450. Using the data of Cohen and Mannering (Mol. Pharmacol., 9 (1973) 383), Testa, (Chem.-Biol. Interact., 34 (1981) 287) has shown that the inhibition of aniline hydroxylation by a series of alcohols can be related to their electronic structure and hydrophobicity (measured by log P, the octanol-water partition coefficient). The mode of binding and effect on spin-state equilibria in cytochrome P-450 by alcohols has been elucidated by Testa, whereas an alternative hypothesis based on connectivity correlations has been reported by Sabljic and Sabljic (Mol. Pharmacol., 23 (1983) 213). The present work shows that the biological response can be explained by calculated electronic structure and molecular shape parameters. Also, one compound (the only tertiary alcohol) from the original set that was not included in Testa's calculations and analysis, is included in this work and its activity successfully calculated. The latter authors, Sabljic and Sabljic, were led to exclude the data for this compound and one other (phenyl methanol) in order to achieve a good correlation with their calculated parameters of molecular structure.
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PMID:Quantitative structure-activity relationships in a series of alcohols exhibiting inhibition of cytochrome P-450-mediated aniline hydroxylation. 362 72

Plasmodium yoelii nigeriensis infection in albino mice significantly altered the hepatic microsomal mixed function oxidase system. Cytochrome P-450 (the terminal monooxygenase) and other monooxygenases, viz. aniline hydroxylase, aminopyrine-N-demethylase and benzo(a)pyrene hydroxylase were significantly lowered while microsomal heme showed 4-fold increase at 80% parasitaemia. Noticeable impairment in the other components like NADH:cytochrome b5 reductase, NADPH:cytochrome c reductase, cytochrome b5 and glucose-6-phosphatase was also observed. Oral treatment of normal and P. y. nigeriensis infected mice with chloroquine (64 mg per kg body weight for 4 days) caused lowering of mixed function oxidase activities which however showed a recovering trend, a week after cessation of treatment.
Mol Biochem Parasitol 1987 Jul
PMID:Effect of Plasmodium yoelii nigeriensis infection and chloroquine on the hepatic mixed function oxidase system of mice. 362 73

Methemoglobinemia after aniline and certain aniline derivatives is thought to be mediated by toxic metabolites formed during the hepatic clearance of the parent compounds. However, three aniline metabolites--phenylhydroxylamine, 2-aminophenol, and 4-aminophenol--catalyze methemoglobin formation in erythrocyte suspensions and, hence, could contribute to methemoglobin formation in vivo after aniline. To determine the relative contributions of these aniline metabolites to aniline-induced methemoglobinemia in rats, we determined time courses of methemoglobinemia in rat erythrocyte suspensions and in rats after treatment with 2- and 4-aminophenol, phenylhydroxylamine, and aniline. The relative potencies for methemoglobin production in vitro after phenylhydroxylamine, 2-aminophenol, and 4-aminophenol were about 10:5:1, based on both peak and area of the methemoglobin versus time curve. Approximate minimum concentrations for observable methemoglobin formation in vitro from these compounds were 20, 50, and 200 microM, respectively. Compared with the in vitro data, the relative potencies of the aminophenols for methemoglobinemia in rats after intraperitoneal injections were reduced with respect to phenylhydroxylamine (to 100:4:1, respectively), apparently as a result of rapid in vivo clearance of the aminophenols. Subsequent experiments, in which the time courses of the aniline metabolites were determined in blood after toxic doses of aniline, demonstrated that only phenylhydroxylamine (measured as phenylhydroxylamine + nitrosobenzene) accumulated to blood levels exceeding the minimum concentration required for methemoglobin production in vitro. In addition, blood levels of phenylhydroxylamine remained in the toxic range throughout most of the methemoglobinemic response after aniline treatment. These data are consistent with phenylhydroxylamine being the sole mediator of aniline-induced methemoglobinemia in these rats.
Mol Pharmacol 1987 Sep
PMID:Contribution of aniline metabolites to aniline-induced methemoglobinemia. 367 Feb 78

Polyclonal and monoclonal antibodies to rabbit liver microsomal alcohol-inducible cytochrome P-450 isozyme 3a (P-450ALC) were used to examine the tissue distribution of the cytochrome. Isozyme 3a or an immunochemically indistinguishable variant of this protein was detected on immunoblots of kidney and nasal mucosa microsomes, but not of microsomes prepared from brain, lung, adrenal, heart, intestine, ovary, spleen, testis, or uterus from untreated or ethanol-treated rabbits. The presence of isozyme 3a was also indicated by inhibition by anti-3a IgG of microsomal aniline hydroxylation and butanol oxidation. The identity of isozyme 3a was further substantiated by peptide-mapping analysis of the immunoaffinity-purified proteins. The amount of isozyme 3a was increased in kidney, but not in nasal microsomes, by chronic ethanol treatment. The induction of isozyme 3a in the kidney was reflected in a more than 2-fold increase in the total rates and a 7-fold increase in the isozyme 3a-dependent rates of aniline and butanol metabolism. Based on immunoblot quantitation, the specific content of isozyme 3a is about 10 pmol/mg of protein in kidney and 80 pmol/mg of protein in nasal microsomes of untreated rabbits. After ethanol treatment of the animals, the content increases to 50 pmol/mg of protein in kidney but is unchanged in nasal microsomes. The presence of isozyme 3a may play a significant role in the toxicity of foreign compounds.
Mol Pharmacol 1986 Oct
PMID:Immunochemical identification of cytochrome P-450 isozyme 3a (P-450ALC) in rabbit nasal and kidney microsomes and evidence for differential induction by alcohol. 376 23

Peattie & Gilbert (1980) have described an accurate and rapid gel method for assessing conformation of individual nucleotides in RNA, based on chemical modification of bases and aniline-induced strand scission. In order to extend this approach to analysis of large RNA molecules, we introduce the use of hybridization of modified RNA with DNA restriction fragments to generate RNA fragments of defined length. In principle, this permits chemical probing of conformation at any position of any RNA molecule for which a cloned DNA coding sequence is available. To illustrate the utility of this method, we use diethylpyrocarbonate to probe the reactivities of adenine residues in Escherichia coli 16 S rRNA under "native" (80 mM-potassium cacodylate (pH 7.0), 20 mM-MgCl2, 300 mM-KCl) and "quasi-secondary" (80 mM-potassium cacodylate (pH 7.0), 1 mM-EDTA) conditions. This study shows that: (1) there is generally good agreement between diethylpyrocarbonate reactivities of adenine residues in naked 16 S rRNA and a secondary structure model based on comparative sequence analysis; of 309 adenine residues probed under native conditions, only four strongly reactive residues are found in helices in the model. (2) Candidates for possible tertiary interactions are identified as adenine residues that are unpaired in the model and unreactive toward diethylpyrocarbonate under native conditions but reactive under quasi-secondary conditions. (3) An unexpectedly stable structure has been identified in the region between positions 109 and 279, where many adenine residues remain unreactive even at 90 degrees C in 80 mM-potassium cacodylate, 1 mM-EDTA. This may correspond to a structural "core" that is important for early events in ribosome assembly.
J Mol Biol 1984 Nov 25
PMID:Chemical probing of conformation in large RNA molecules. Analysis of 16 S ribosomal RNA using diethylpyrocarbonate. 621 Mar 72

Two forms of cytochrome P-450 have been purified to electrophoretic homogeneity from hepatic microsomes of rabbits treated with imidazole. Several criteria indicate that the cytochrome of higher electrophoretic mobility is identical with ethanol-inducible isozyme 3a. "Imidazole-3a" and "ethanol-3a" exhibit the same chromatographic characteristics and have identical electrophoretic mobilities upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Furthermore, the two protein preparations have the same absorbance maxima and absorption coefficients in the oxidized, reduced, and reduced-CO states. A single immunoprecipitin band exhibiting complete identity was observed upon reaction of imidazole-3a and ethanol-3a with the immunoglobulin G fraction from sheep immunized with the latter protein. The amino acid composition and first 10 residues of the amino terminus of the two protein preparations are indistinguishable, as are the high-performance liquid chromatographic maps of the peptides obtained upon cleavage with trypsin, Staphylococcus aureus V8 protease, or Lys C endoproteinase . Furthermore, these preparations have very similar activities in the oxidation of ethanol to acetaldehyde and the p-hydroxylation of aniline. Evidence was obtained that the cytochrome of lower electrophoretic mobility isolated from imidazole-treated rabbits is probably identical with isozyme 6; the spectral characteristics, amino acid composition, and carboxyl-terminal sequence are described. As an inducer, imidazole has the advantage over ethanol of being less variable in its effects and requiring a shorter period of treatment. From the resulting liver microsomes, one can readily isolate, in addition to P-450 isozymes 3a and 6, isozymes 3c and 4 as well as epoxide hydrolase.
Mol Pharmacol 1984 May
PMID:Purification of liver microsomal cytochrome P-450 isozymes 3a and 6 from imidazole-treated rabbits. Evidence for the identity of isozyme 3a with the form obtained by ethanol treatment. 642 1

Hemoglobin has been characterized as a monooxygenase-like catalyst of aniline hydroxylation both in reconstituted systems [ Mieyal et al. J. Biol. Chem. 251:3436-3441 (1976)] and in intact erythrocytes [ Blisard and Mieyal , J. Biol. Chem. 254:5104-5110 (1979)]. In this report, the monooxygenase activity of isolated hemoglobin (Hb) in the reconstituted system, which includes NADPH and cytochrome P-450 reductase, was shown to include N- and O-demethylation reactions besides p-hydroxylation, and to extend to other typical cytochrome P-450 substrates such as benzphetamine and p-nitroanisole. Some substrates were tested also with intact erythrocytes. Those which were metabolized displayed relative activities qualitatively similar to the pattern with isolated Hb. With isolated hemoglobin, complete kinetic analysis was carried out for 10 different reactions. The Km and Vmax values varied broadly, so that the efficiencies of the reactions (Vmax/Km) encompassed a range greater than 40,000. The most efficient reaction was O-demethylation of p-nitroanisole; the highest Vmax was observed for the O-demethylation of p-anisidine. The efficiencies (Vmax/Km) for a series of anisole derivatives (p-NH2,p-OH, p-H,p-NO2) was found to be quite sensitive to the electron-withdrawing effect of the p-substituent, i.e. a linear Hammett sigma rho relationship (log Vmax/Km versus sigma) was observed (p = 1.43). Metabolism of N-methylaniline by hemoglobin displayed distinct regioselectivity , with N-demethylation being favored over p-hydroxylation. Separate Km and Vmax values were observed for these two reactions of the single substrate, suggesting that distinct ternary O2-Hb-substrate complexes mediate the two reactions. In separate experiments, the various substrates were tested for their ability to accelerate autooxidation of HbO2 in the absence of NADPH and reductase. Aniline and its derivatives induced autooxidation with a concentration dependence matching their Km values for the corresponding hydroxylation reactions with the complete catalytic system. With the exception of p-hydroxyanisole, none of the other substrates accelerated autooxidation of HbO2. Hence this phenomenon cannot be an indicator of potential monooxygenase reactivity with hemoglobin. The broad and regioselective activities observed for hemoglobin resemble the characteristics of the authentic monooxygenase enzyme cytochrome P-450.
Mol Pharmacol 1984 May
PMID:Substrate specificity of the monooxygenase activity of hemoglobin. 672 68

The aniline hydroxylase activity of adult rabbit hemolysates (1 mM with respect to hemoglobin concentration) was found to be 80 pmoles of p-aminophenol formed per minute per milliliter. This value is comparable to that observed for adult human hemolysates. The characteristics of this O2-requiring aromatic p-hydroxylation reaction are typical of the monooxygenase reactions catalyzed by the liver microsomal cytochrome P-450 system. Both systems are inhibited by carbon monoxide, which coordinates directly with the heme iron atoms of the respective hemoproteins. With the use of 13C-NMR spectroscopy, separate, well-resolved signals were observed for 13C-enriched carbon monoxide bound to the alpha- and beta-subunits of the tetrameric (alpha 2 beta 2) rabbit hemoglobin. By appropriately adjusting conditions, the hemoglobin was converted into hybrids of ligation varying from full oxygenation to intermediate forms in which the oxygen was progressively replaced by 13CO, first on the beta-subunits, then on the alpha-subunits until full CO ligation was accomplished. The state of ligation of the hemoglobin in each case was determined from the integrated areas of the signals in the corresponding 13C-NMR spectra. The corresponding aniline hydroxylase activity of the rabbit hemolysates containing such hybrids revealed that the monooxygenase activity of intact tetrameric hemoglobin is determined predominantly (if not exclusively) by the ligation of the beta-subunits. To the best of our knowledge, this is the first report of differential subunit behavior for a monooxygenase-like enzymatic activity.
Mol Pharmacol 1982 Jan
PMID:Subunit selectivity in the monooxygenase-like activity of tetrameric hemoglobin. 713 51

p-Aminophenol (PAP), a metabolite of aniline and acetaminophen, has been reported to be mutagenic in the L5178Y mouse lymphoma assay, but not in the CHO/HGPRT assay. In the present study, the effects of PAP in these two cells lines were examined to determine if the difference in activity is related to an intrinsic difference in the cell lines. CHO and L5178Y tk +/- mouse lymphoma cells were treated with PAP for 4 hr and assayed for 3 genetic endpoints: gene mutation at the HGPRT or TK locus, respectively; chromosomal aberrations at approximately 20 hr after initiation of treatment; and single-strand DNA breaks as detected by the single cell electrophoresis assay immediately after treatment. All treatments were conducted in the absence of S9. There was a dose-related, significant increase in TFT-resistant mouse lymphoma cells at dose levels that reduced survival to < or = 50% of concurrent controls. In CHO cells, however, there was no increase in thioguanine-resistant cells at dose levels that reduced cell survival to < 20%. These results are consistent with published reports on PAP. While the CHO cells were slightly more resistant to the toxic effects of PAP, the dose levels used in the two cell lines did not differ by more than 2-fold. At equivalent survival levels, PAP induced a significant (up to 20% aberrant cells) number of aberrations, primarily complex rearrangements, in both cell lines. In the single cell electrophoresis assay, there was a reproducible dose-related increase in cells with single-strand DNA breaks with both the L5178Y cells and the CHO cells. The induction of single-strand breaks and chromosome aberrations by PAP suggests that, mechanistically, PAP produces similar genetic damage in both CHO and L5178Y cell lines, but intrinsic differences between assay systems are responsible for the divergent gene mutation results.
Environ Mol Mutagen 1995
PMID:Genotoxic effects of p-aminophenol in Chinese hamster ovary and mouse lymphoma cells: results of a multiple endpoint test. 755 13

A very active cell-free translation system was prepared from Agrobacterium tumefaciens, a bacterium broadly used to transfect plant cells to introduce foreign genes and one that produces tumours in plants. Once optimized for Mg2+, NH4+, high speed supernatant S 370, purified ribosomes and time, the system translates polyuridylic acid very efficiently. A. tumefaciens purified ribosomes were inhibited in vitro by several well-known translational inhibitors including some ribosome-inactivating proteins. Treatment of A. tumefaciens purified ribosomes with type 1-RIP crotin 2 lead to the depurination of the 23S rRNA which, upon treatment with acid aniline, released a diagnostic RNA fragment of about 235 nucleotides.
Cell Mol Biol (Noisy-le-grand) 1993 Sep
PMID:Preparation, optimization and characterization of a polyphenylalanine synthetizing system from Agrobacterium tumefaciens. 769 97


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