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The reductive addition of GSH to p-benzoquinones, 2-hydroxy-p-benzoquinone, and 2,3-epoxy-p-benzoquinones with different degree of methyl substitution was studied in terms of absorption spectral changes and autoxidation reactions. The nucleophilic addition of GSH to p-benzoquinone yields a glutathionyl-p-benzohydroquinone product with maximal absorption at lambda 303nm. This compound autoxidizes slowly--but at a rate 8-fold higher than the parent hydroquinone--to glutathionyl-p-benzoquinone, which reveals maximal absorption at lambda 367 nm. The autoxidation of the glutathionyl derivative is accompanied by O2 consumption and H2O2 formation. The nucleophilic addition of GSH to either 2-hydroxy-p-benzoquinone or 2,3-epoxy-p-benzoquinone yields the same primary molecular product, 2-hydroxy-5-glutathionyl-p-benzohydroquinone, a compound that shows maximal absorption at lambda 300 nm and autoxidizes at rates substantially higher (44-fold) than the parent glutathionyl hydroquinone lacking a -OH substituent. The autoxidation product, 2-hydroxy-5-glutathionyl-p-benzoquinone, reveals maximal absorbance at lambda 343 nm as well as a resolved absorption band at longer wavelengths (lambda 520 nm), the latter contributed by the -OH substituent. The glutathionyl substituent exerted only minor changes in the reduction potential of the quinones, whereas the -OH substituent lowered significantly the half-wave reduction potential, as measured in aqueous solutions. The rate of autoxidation was markedly enhanced by both substituents as follows: hydroxy-glutathionyl-p-benzohydroquinone much greater than hydroxy-p-benzohydroquinone much greater than glutathionyl-p-benzohydroquinone greater than p-benzohydroquinone. Superoxide dismutase enhanced the rate of autoxidation of p-benzohydroquinone and its glutathionyl adduct, whereas it inhibited autoxidation of the hydroxy derivatives with or without glutathionyl substitution. The biochemical significance of these results is discussed in terms of the pro-oxidant character of the reductive addition of GSH to p-benzoquinones, alpha-hydroxyquinones, and quinone epoxides.
Restricted and unrestricted (U) Hartree-Fock (HF), second-order Møller-Plesset perturbation (MP2), density functional (DF), hybrid HF/DF and semiempirical (half-electron (HE) method) models have been used to calculate adiabatic electron affinities (EAad values) of p-benzoquinone (I), p-benzoquinone imine (VI) and p-benzoquinone diimine (XI), as well as expectation values ( ) and spin density distributions in the radical anions of I, VI and XI. The AM1/AM1-HE and ab initio calculated structures are found to be in accord with each other. The ROHF/6-31G(d) method gave the poorest EAad result. The UHF and UMP2 wave functions were found to be substantially spin contaminated (for the radicals) and the accuracies of the EAad values calculated were also poor. The use of molecular energies obtained after spin annihilation did not lead to significant improvement of the UHF and UMP2 results. In contrast to the ROHF, UHF and UMP2 results, the DF(USVWN, UBVWN, UBLYP) and hybrid HF/DF(UB3LYP) methods, as well as the AM1-HE, gave much better results. The calculated EAad values decreased, as predicted by most of the models, in the order EAad(I) > EAad(VI) > EAad(XI). The differences in the EAs, EAad(I)-EAad(VI) and EAad(I)-EAad(XI), were consistently predicted to be about 8-9 and 17-18 kcal/mol, respectively, by the DF, B3LYP and AM1-HE models. The performance of the PM3 and SAM1 models was not as good as the AM1 model. Of all the methods tested, the B3LYP/6-311G(d,p) model is concluded to give the most accurate quantitative trend (I(42.6) > VI(33.1) > XI(23.7)) in EAad. The predicted trend in EA can satisfactorily be rationalized by the calculated LUMO orbital energies, atomic charges and spin density distributions. Analysis of the spin density data predicts that phenoxyl- and anilino-type radical anions predominate in the p-benzosemiquinones of I and XI, respectively, while both phenoxyl- and anilino-type radicals contribute to the structure of the p-benzosemiquinone of VI, with the anilino-type predominating.
The reaction between H2O2 and p-benzoquinone proceeds with consumption of both reactants with second order rate constants of 1.66- and 0.77 M-1S-1, respectively. The process is mainly supported by oxygen addition reactions to the quinone resulting in the formation of both 2,3-epoxy-p-benzoquinone and 2-OH-p-benzoquinone. The former product accumulates in the assay mixture without participating in further reactions. The formation of the latter product implies free radical intermediates such as 2-OH-p-benzosemiquinone anion, which supports the generation of electronically excited states upon its oxidation by H2O2, presumably as part of an organic Fenton reaction. The relaxation of the excited state is accompanied by photoemission at 485-530 nm. Glutathione was found to counteract the oxidative aspects of the reaction between p-benzoquinone and H2O2 by a series of processes involving (a) a rapid reductive addition to the quinone with formation of a substituted p-benzohydroquinone; (b) an effective quenching of photoemission, which might be attributed to the deactivation of the excited state by the p-benzohydroquinone-glutathione adduct, and (c) the decomposition of the formed 2,3-epoxy-p-benzoquinone, also by reductive cleavage of the epoxide ring.
The reaction of the common pain reliever acetaminophen (paracetamol, 4-acetamidophenol) with hypochlorite was investigated over time under conditions that simulate wastewater disinfection. Initially, the reaction was studied in pure water at neutral pH (7.0), a range of reaction times (2-90 min), and a molar excess of hypochlorite (2-57 times) relative to the acetaminophen concentration. The reaction was monitored using reversed-phase liquid chromatography (LC) with ultraviolet absorbance, electrochemical, and mass spectrometric detection. At 1 micromol/L (150 ppb) and 10 micromol/L (1.5 ppm) levels, acetaminophen readily reacted to form at least 11 discernible products, all of which exhibited greater LC retention than the parent. Two of the products were unequivocally identified as the toxic compounds 1,4-benzoquinone and N-acetyl-p-benzoquinone imine (NAPQI), which is the toxicant associated with lethality in acetaminophen overdoses. With a hypochlorite dose of 57 micromol/L (4 ppm as Cl2), 88% of the acetaminophen (10 micromol/L initial) was transformed in 1 h. The two quinoidal oxidation products 1,4-benzoquinone and NAPQI accounted for 25% and 1.5% of the initial acetaminophen concentration, respectively, at a 1 h reaction time. Other products that were identified included two ring chlorination products, chloro-4-acetamidophenol and dichloro-4-acetamidophenol, which combined were approximately 7% of the initial acetaminophen concentration at 1 h. The reaction was also studied in wastewater, where similar reactivity was noted. These results demonstrate that acetaminophen is likely to be transformed significantly during wastewater chlorination. The reactivity of the chlorine-transformation products was also studied with sulfite to simulate dechlorination, and 1,4-benzoquinone and NAPQI were completely reduced.
MNDO calculations have been carried out for the contact sensitizers 2,6-dimethoxy-1,4-benzoquinone (6) and 2-methoxy-6-methyl-1,4-benzoquinone (10) and for 2,5-dimethoxy-1,4-benzoquinone (7), which is nonallergenic in contrast to thymoquinone (8) (2-methyl-5-isopropyl-1,4-benzoquinone), which is a relatively strong contact allergen. Theoretical results indicate that the conformational flexibility of methoxy groups substituted at the quinone rings influences the electronic properties of these compounds, in particular their reactivity with regard to nucleophiles. According to theory, 6, 10, and 8 should possess a pronounced reactivity toward nucleophiles while 7 should resist nucleophilic attack. Hence, the allergenic capacity of a quinone seems to depend on their binding interactions with nucleophiles such as amino or thio groups of amino acids.
The ubiquinone precursors, 2-octaprenyl-6-methoxy-1,4-benzoquinone and 2-octaprenyl-3-methyl-6-methoxy-1,4-benzoquinone, were isolated from ubiquinone-deficient mutants of Escherichia coli and identified by nuclear magnetic resonance and mass spectrometry. Mutants accumulating 2-octaprenyl-6-methoxy-1,4-benzoquinone and 2-octaprenyl-3-methyl-6-methoxy-1,4-benzoquinone were shown to carry mutations in genes designated ubiE and ubiF, respectively. The ubiE gene was shown to be cotransducible with metE (minute 75) and close to two other genes concerned with ubiquinone biosynthesis. The ubiF gene was located close to minute 16 by cotransduction with the lip, gltA, and entA genes.
6-(10-Hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (idebenone) has been found to have a membrane-stabilizing activity in studies using lysosomes. Using dimyristoyl L-alpha-phosphatidylcholine (DMPC) as a substrate, the effects of idebenone and related benzoquinones on phospholipid digestion by phospholipase A2 (PLA2) was investigated. Free myristic acid, released from DMPC upon PLA2 treatment, was anthrylmethylated with 9-anthryldiazomethane (ADAM) and determined by reversed-phase HPLC. Idebenone and a related benzoquinone, 2,3-dimethoxy-5-methyl-6-(10-morpholinodecyl)-1, 4-benzquinone hydrochloride (QS-10.Mor), inhibited the hydrolysis of the substrate with PLA2 in a dose-dependent manner. It is suggested that the effect of idebenone on PLA2, in addition to its antioxidant activity lipid peroxidation, can be attributed to membrane-stabilizing activity.
An efficient method for the synthesis of diamino-o-benzoquinone based on the Michael reaction of electrochemically generated o-benzoquinone with azide ion is described, as well as an estimation of the homogeneous rate constant (k(obs)) of the reaction of o-benzoquinone with azide ion by the digital-simulation method.
A triple mutant of rat liver glutathione S-transferase 3-3 that has all three cysteine residues replaced with serine (CallS) and a quadruple mutant with a Tyr-115 to phenylalanine substitution on CallS (CallSY115F) were reacted with 2-(S-glutathionyl)-3,5,6-trichloro-1,4-benzoquinone (GS-1,4-TCBQ). The modified proteins were analysed on a triple-quadrupole mass spectrometer equipped with an electrospray ionization source. At an enzyme: GS-1,4-TCBQ ratio of 1:10, the enzymes were modified at multiple sites. Covalent attachment of a single inhibitor on to the protein was achieved by lowering the enzyme: GS-1,4-TCBQ ratio to 1:1. Results from m.s. analyses suggest that the inhibitor on the CallSY115F mutant exists as a glutathionyl dichlorobenzoquinone derivative. The modifiers of the CallS mutants are glutathionyl monochlorobenzoquinone derivatives. Therefore, GS-1,4-TCBQ reacts at a single site on CallSY115F, but probably cross-links two regions on wild-type and CallS mutant. To confirm our observation, CallS was modified with 1-chloro2,4-dinitrobenzene, which specifically labels Tyr-115, before reacting with GS-1,4-TCBQ. The inhibitor formed a glutathionyl dichlorobenzoquinone adduct on the dinitrophenyl-CallS mutant. In addition, the benzoquinone derivative on the protein can be partially removed by 1-chloro-2,4-dinitrobenzene. Peptide mapping and sequencing analysis of the GS-1,4-TCBQ-modified CallS mutant revealed that the C-terminal 16-amino-acid fragment is labelled. Molecular modelling suggests the C(5) and C(6) on the benzoquinone ring of the inhibitor interact with the oxygen atoms of Tyr-115 and Ser-209 respectively.
1,4-benzoquinone (BQ) and 2,5-dimethyl-1,4-benzoquinone (DMBQ) were studied as inhibitors of jack bean urease in 50 mM phosphate buffer, pH 7.0. The mechanisms of inhibition were evaluated by progress curves studies and steady-state approach to data achieved by preincubation of the enzyme with the inhibitor. The obtained reaction progress curves were time-dependent and characteristic of slow-binding inhibition. The effects of different concentrations of BQ and DMBQ on the initial and steady-state velocities as well as the apparent first-order velocity constants obeyed the relationships of two-step enzyme-inhibitor interaction, qualified as mechanism B. The rapid formation of an initial BQ-urease complex with an inhibition constant of Ki = 0.031 mM was followed by a slow isomerization into the final BQ-urease complex with the overall inhibition constant of Ki* = 4.5 x 10(-5) mM. The respective inhibition constants for DMBQ were Ki = 0.42 mM, Ki* = 1.2 x 10(-3) mM. The rate constants of the inhibitor-urease isomerization indicated that forward processes were rapid in contrast to slow reverse reactions. The overall inhibition constants obtained by the steady-state analysis were found to be 5.1 x 10(-5) mM for BQ and 0.98 x 10(-3) mM for DMBQ. BQ was found to be a much stronger inhibitor of urease than DMBQ. A test, based on reaction with L-cysteine, confirmed the essential role of the sulfhydryl group in the inhibition of urease by BQ and DMBQ.
Studies of absorbance related to the cytochrome b-559 photooxidation induced by FCCP, with and without addition of 3-p-chlorophenyl-1, 1-dimethylurea (CMU), DBMIB or p-benzoquinone, in whole cells and in chloroplast fragments of Chlamydomonas reinhardti, were carried out. In addition to the wild type, three strains of non-photosynthetic mutants were used: Fl 5, which lacks P 700; Fl 9 and Fl 15, which are deficient in bound cytochrome c-553 and in cytochrome b-563. In the presence of FCCP, whole cells and chloroplast fragments of the four strains showed a System II-dependent photooxidation of cytochrome b-559. This photooxidation was inhibited by CMU but it occurred again in presence of FCCP, CMU and DBMIB. In chloroplast fragments, cytochrome b-559 photooxidation was also inhibited by an excess of FCCP; it was recovered, likewise, by addition of DBMIB. In whole cells, the highest measured redox changes were: 1 mu mol oxidized cytochrome b-559 per 1 mmol chlorophyll, corresponding approximately to about one seventh (wild type, Fl5) or one fifth (Fl 9, Fl 15) of the total amount of this cytochrome. Another kind of cytochrome b-559 photooxidation, CMU-insensitive, also occurred in the mutants Fl 9 and Fl 15 and in the wild type, but not in the mutant Fl 5. This latter kind of photooxidation was observed with chloroplast fragments in the presence of FCCP and CMU and also with whole cells in the presence of FCCP, CMU and p-benzoquinone. These reactions can be attributed to the Photosystem I; they do not require the intervention of the cytochrome c-553. A high-potential form of cytochrome b-559, hydroquinone-reducible, was involved in these two kinds of photooxidation. In addition, a lower potential form, reducible only by ascorbate, appeared to be able to interfere also. An interpretation is attempted, taking into consideration the various effects of FCCP and DBMIB, at different concentrations, on photosynthetic electron transport.
Tetrachloro-o-benzoquinone (TCoBQ) and tetrachloro-p-benzoquinone (TCpBQ) were studied as inhibitors of jack bean urease in 20 mM phosphate buffer, pH 7.0, 1 mM EDTA, 25 degrees C. The mechanisms of inhibition were evaluated by analysis of the progress curves obtained with two procedures: the reaction initiated by addition of the enzyme and the reaction initiated by addition of the substrate after preincubation of the enzyme with the inhibitor. The obtained results were characteristic of slow-binding inhibition. The effects of different inhibitor concentrations on the initial and steady-state velocities obeyed the relationships of two-step enzyme-inhibitor interaction, qualified as mechanism B. It was found that TCoBQ and TCpBQ are strong urease inhibitors. TCpBQ is more effective than TCoBQ with the overall inhibition constant of K(i)* = 4.5 x 10(-7) mM. The respective inhibition constant of TCoBQ was equal to: K(i)* = 2.4 x 10(-6) mM. The protective experiment proved that the urease active site is involved in the tetrachlorobenzoquinone inhibition process. High effectiveness of thiol protectors against inhibition by TCoBQ and TCpBQ indicates the strategic role of the active site sulfhydryl group in the blocking process. The stability of the complexes: urease-TCoBQ and urease-TCpBQ was tested in two ways: by dilution or addition of dithiothreitol. No recovery of urease activity bound in the urease-inhibitor complexes proves that the complexes are stable and strong.
Benzene is a carcinogen in rodents and a cause of bone marrow toxicity and leukemia in humans. p-Benzoquinone (p-BQ) is one of the stable metabolites of benzene, as well as of a number of drugs and other chemicals. 2'-Deoxycytidine (dC) and 2'-deoxyadenosine (dA) were allowed to react with p-BQ in aqueous solution at pH 7.4 and 4.5. The yields were considerably higher at pH 4.5 than at pH 7.4, as indicated by HPLC analysis. The desired products were isolated by column chromatography on silica gel or cellulose. Identification was done by FAB-MS, 1H NMR, and UV spectroscopy. The reaction of p-BQ with dC and dA at pH 4.5 produced the exocyclic compounds 3-hydroxy-1,N4-benzetheno-2'-deoxycytidine (p-BQ-dC), and 9-hydroxy-1,N6-benzetheno-2'-deoxyadenosine (p-BQ-dA), respectively, in a large scale and high yield. These adducts have been previously made in a microgram scale as the 3'-phosphate for 32P-postlabeling studies of their incidence in DNA. The p-BQ-dC and p-BQ-dA adducts have, in addition to the two hydroxyl groups of deoxyribose, one newly formed hydroxyl group at the C-3 or C-9 of the exocyclic base of each product respectively. Incorporation of these adducts into oligonucleotides as the phosphoramidite requires the protection of all three hydroxyl groups in these compounds. The exocyclic hydroxyl on the base has been successfully protected by acylation after protecting the 5'- and the 3'-hydroxyl groups of the sugar moiety with a 4,4'-dimethoxytrityl group and a cyanoethyl N,N-diisopropylphosphoramidite group, respectively. For the first time, to our knowledge, the fully protected phosphoramidites of p-BQ-dC and p-BQ-dA were prepared and incorporated site-specifically into a series of oligonucleotides. The coupling efficiency was very high (> 98%). However, deprotection of the DNA oligomers with ammonia produced only 50% of the desired oligomers containing the adduct. In contrast, when 10% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol at room temperature was used, only the desired oligomers were detected by HPLC. Thus, by deprotecting the oligomers with methoxide ions (DBU/methanol) and avoiding the use of ammonia, a high yield of modified DNA was obtained. After purification of these oligomers by HPLC, they were hydrolyzed enzymatically and analyzed by HPLC, which confirmed the base composition and the incorporation of the adducts. The mass spectroscopic analysis of the DNA oligomers was confirmed by electrospray MS. These oligomers are now under investigation for their biochemical properties.
The metabolic efficiency of seven derivatives of 1,4-benzoquinone (BQ) by yeast cells and the oxidative characteristics of the corresponding hydroquinones (HQs) were studied by electrochemical, spectrophotometric and chemiluminescent methods. The spectrophotometric method was based on the reduction of a tetrazolium salt to formazan dye during the autoxidation of HQs generated by yeast cells under alkaline conditions. The amounts of HQs detected directly by the electrochemical method did not agree with those calculated from the formazan dye obtained by the spectrophotometric method. A tetrazolium salt was reduced to a formazan dye by both the superoxide anion radical (O2-*) generated during the autoxidation of 2,3,5,6-tetramethyl-1,4-HQ and by HQ itself. Little formazan dye was formed, and hydrogen peroxide (H2O2) was then finally produced during the autoxidation of 1,4-HQ or 2-methyl-1,4-HQ. Formazan dye and H2O2 were generated at a certain ratio during the autoxidation of derivatives of dimethyl-1,4-HQ or 2,3,5-trimethyl-1,4-HQ. The analytical method based on chemiluminescence with lucigenin and 2,3,5,6-tetramethyl-1,4-BQ was applied to highly sensitive measurement of the yeast cell density. A linear relationship between the chemiluminescence intensity and viable cell density was obtained in the range of 1.2 x 10(3) - 4.8 x 10(4) cells/ml. The detection limit was 4.8 x 10(2) cells/ml.
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