Quinone metabolism

Workman, P. Enzyme-directed bioreductive drug development revisted a commentary on recent progress and future prospects with emphasis on quinone anticancer agents and quinone metabolizing enzymes, particularly DT-diaphorase. Oncol. Res. 1994, 6, 461 175. 

Although all quinones have the same functional group, their physicochemical behavior and mechanisms of toxicity vary due to the presence of different substituents. Thus, the cellular aspects of quinone metabolism are diverse, and a single mechanism explaining these actions has not yet been identified. Furthermore, it is noteworthy that the cytotoxicity of some xenobiotic compomids, such as benzene, benzo[a]pyrene, and 1-naphthol, may partly be caused by metabolic conversion of these compoimds to quinones (Snyder et al, 1987 Zheng et al, 1997). 

Benzo[b]thiophene-2,3-quinone, 5-chloro-oxidation, 4, 824 Benzothiophenes, 4, 863-934 biological activity, 4, 911-913 intramolecular acylation, 4, 761 mass spectrometry, 4, 739 metabolism, 1, 242 phosphorescence, 4, 16 reactivity, 4, 741-861 spectroscopy, 4, 713-740 structure, 4, 713-740 substituents reactivity, 4, 796-839... 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

Peroxidases are found in milk and in leukocytes, platelets, and other tissues involved in eicosanoid metabolism (Chapter 23). The prosthetic group is protoheme. In the reaction catalyzed by peroxidase, hydrogen peroxide is reduced at the expense of several substances that will act as electron acceptors, such as ascorbate, quinones, and cytochrome c. The reaction catalyzed by peroxidase is complex, but the overall reaction is as follows ... 

The shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

The second study was performed using either cytosolic or microsomal fractions from rat liver as the in vitro metabolic mammal models [238]. The studied compound, benzofuroxan (128, Fig. 20), is metabolized to o-quinone dioxime and 2,3-diaminophenazine (Scheme 4). 

K. Mizutani, T. Electronic and structural requirements for metabolic activation of butylated hydroxytoluene analogs to their quinone methides, intermediates responsible for lung toxicity in mice. Biol. Pharm. Bull. 1997, 20, 571-573. (c) McCracken, P. G. Bolton, J. L. Thatcher, G. R. J. Covalent modification of proteins and peptides by the quinone methide from 2-rm-butyl-4,6-dimethylphenol selectivity and reactivity with respect to competitive hydration. J. Org. Chem. 1997, 62, 1820-1825. (d) Reed, M. Thompson, D. C. Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di- m-butyl-4-methylphenol (BHT). Chem. Res. Toxicol. 1997, 10, 1109-1117. (e) Lewis, M. A. Yoerg, D. G. Bolton, J. L. Thompson, J. Alkylation of 2 -deoxynucleosides and DNA by quinone methides derived from 2,6-di- m-butyl-4-methylphenol. Chem. Res. Toxicol. 1996, 9, 1368-1374. 

The results presented above indicate that the previously unknown head-to-tail polymerization is the major reaction product of the iminium methide species. To investigate the generality of this reaction, we next studied a neutral ene-imine species shown in Scheme 7.9.48 As illustrated in this scheme, the generation of this reactive species requires quinone reduction followed by elimination of acetic acid. The ene-imine is structurally related to the methyleneindolenine reactive species that is a metabolic oxidation product of 3-methylindole (Scheme 7.9).57 59... 

Acolbifene is also metabolized to a QM (Scheme 10.10)64 formed by oxidation at the C-17 methyl group. This QM is considerably more reactive compared to the tamoxifen quinone methide, which indicates that the acolbifene quinone methide is an electrophile of intermediate stability (Table 10.2). In addition, the acolbifene QM was determined to react with deoxynucleosides, with one of the major adducts resulting from reaction with the exocyclic amino group of adenine.64... 

Monks, T. J. Jones, D. C. The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. Curr. Drug Metab. 2002, 3, 425M-38. 

Kassahun, K. Pearson, P. G. Tang, W. McIntosh, I. Leung, K. Elmore, C. Dean, D. Wang, R. Doss, G. Baillie, T. A. Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem. Res. Toxicol. 2001, 14, 62-70. 

Fan, P. W. Zhang, F. Bolton, J. L. 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. Chem. Res. Toxicol. 2000, 13, 45-52. 

E) coumarins, (F) quinones, (G) flavonoids, (H) tannins, (I) alkaloids, (J) terpenoids and steroids and (K) miscellaneous and unknowns. Although many of these compounds are secondary products of plant metabolism, several are also degradation products which occur in the presence of microbial enzymes. 

Drosophila Ddc is expressed primarily in the CNS and the hypoderm, the epithelial layer of the fly that secretes the cuticle. In the CNS, Ddc is expressed in a small subset of neurons that produce either dopamine or serotonin (Budnik and White, 1988 Valles and White, 1988). In the hypoderm, Ddc expression leads to synthesis of dopamine, which is further metabolized into quinones that have a vital function in the cross-linking, hardening, and pigmentation of the fly cuticle (Wright, 1987). The developmental profile of DDC activity in these two tissues is quite different (Hirsh, 1986). DDC is first detected during late embryo-... 

Quinone oxidoreductase, Sulfotransferase Drug metabolism 6 out of 22 coding region SNPs gave amino acid substitutions 15... 

Metabolic Formation of Quinones by an Initial One-Electron Oxidation of BP... 

Metabolism of BP mediated by the cytochrome P-450 monooxygenase system forms three classes of products phenols, dihydrodiols and quinones. Formation of phenols and dihydrodiols is obtained by an initial electrophilic attack of an enzyme-generated oxygen atom. 

The first line of evidence derives from the predominant formation of quinones when metabolism of BP is conducted under peroxi-datic conditions, namely by prostaglandin H synthase (21) or by cytochrome P-450 with cumene hydroperoxide as cofactor T22). Under these metabolic conditions one-electron oxidation is the preponderant mechanism of activation. 

Second, metabolism of 6-fluoroBP by rat liver microsomes yields the same BP quinones obtained in the metabolism of BP (23). This suggests that these products are formed by an initial attack of a nucleophilic oxygen atom at C-6 in the 6-fluoroBP radical cation with displacement of the fluoro atom. In fact, when 6-fluoroBP is treated with the one-electron oxidant Mn(0Ac)3, the major products obtained are 6-acetoxyBP and a mixture of 1,6- and 3,6-diacetoxyBP (15), indicating that reaction occurs via an initial attack of acetate ion at C-6 of the 6-fluoroBP radical cation. On the other hand electrophilic substitution of 6-fluoroBP with bromine or deuterium ion shows no displacement of fluorine at C-6, although in both cases substitution occurs at C-l and/or C-3. These results indicate that... 

Finally, we have studied the metabolism of a series of PAH with decreasing IP. In these metabolic studies with Aroclor-induced rat liver microsomes, the formation of quinones was measured in the presence of NADPH or cumene hydroperoxide as cofactor. 

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