Identification of Catechol and Hydroquinone Metabolites of 4-Monochlorobiphenyl

McLean, Mitch R.; Bauer, Udo; Amaro, and Anthony R.; Robertson, Larry W.

doi:10.1021/tx950083a

Cited by 144 publications

(188 citation statements)

References 36 publications

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“…The structure and coupling constants shown in Fig. 3B are identical to those already reported for 3,4-dihydroxy-4=-chlorobiphenyl in the same solvent (35). The accumulation of metabolites 4 and 7 in biphenyl-induced cell suspensions of strain B356 may be explained by the inability of B356 BphC to metabolize meta-para-dihydroxybiphenyls during the incubation period (36).…”

Section: Resultssupporting

confidence: 81%

Metabolism of Doubly para -Substituted Hydroxychlorobiphenyls by Bacterial Biphenyl Dioxygenases

Pham

Sondossi

Sylvestre

2015

Appl Environ Microbiol

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In this work, we examined the profile of metabolites produced from the doubly para-substituted biphenyl analogs 4,4=-dihydroxybiphenyl, 4-hydroxy-4=-chlorobiphenyl, 3-hydroxy-4,4=-dichlorobiphenyl, and 3,3=-dihydroxy-4,4=-chlorobiphenyl by biphenyl-induced Pandoraea pnomenusa B356 and by its biphenyl dioxygenase (BPDO). 4-Hydroxy-4=-chlorobiphenyl was hydroxylated principally through a 2,3-dioxygenation of the hydroxylated ring to generate 2,3-dihydro-2,3,4-trihydroxy-4=-chlorobiphenyl and 3,4-dihydroxy-4=-chlorobiphenyl after the removal of water. The former was further oxidized by the biphenyl dioxygenase to produce ultimately 3,4,5-trihydroxy-4=-chlorobiphenyl, a dead-end metabolite. 3-Hydroxy-4,4=-dichlorobiphenyl was oxygenated on both rings. Hydroxylation of the nonhydroxylated ring generated 2,3,3=-trihydroxy-4=-chlorobiphenyl with concomitant dechlorination, and 2,3,3=-trihydroxy-4=-chlorobiphenyl was ultimately metabolized to 2-hydroxy-4-chlorobenzoate, but hydroxylation of the hydroxylated ring generated dead-end metabolites. 3,3=-Dihydroxy-4,4=-dichlorobiphenyl was principally metabolized through a 2,3-dioxygenation to generate 2,3-dihydro-2,3,3=-trihydroxy-4,4=-dichlorobiphenyl, which was ultimately converted to 3-hydroxy-4-chlorobenzoate. Similar metabolites were produced when the biphenyl dioxygenase of Burkholderia xenovorans LB400 was used to catalyze the reactions, except that for the three substrates used, the BPDO of LB400 was less efficient than that of B356, and unlike that of B356, it was unable to further oxidize the initial reaction products. Together the data show that BPDO oxidation of doubly para-substituted hydroxychlorobiphenyls may generate nonnegligible amounts of dead-end metabolites. Therefore, biphenyl dioxygenase could produce metabolites other than those expected, corresponding to dihydrodihydroxy metabolites from initial doubly para-substituted substrates. This finding shows that a clear picture of the fate of polychlorinated biphenyls in contaminated sites will require more insights into the bacterial metabolism of hydroxychlorobiphenyls and the chemistry of the dihydrodihydroxylated metabolites derived from them.T he toxicity of hydroxybiphenyls in antimicrobial preparations used as biocides has been exploited for many years (1). In addition, hydroxybiphenyls are key intermediates produced from multiple sources. For example, they are produced from the microbial metabolism of dibenzofuran, fluorene, and carbazole (2, 3). In polychlorinated biphenyl (PCB)-contaminated sites, hydroxychlorobiphenyls are generated by the bacterial biphenyl catabolic enzymes (4) and by plant enzymatic systems (5, 6). In addition, hydroxychlorobiphenyls may be produced in significant amounts by abiotic processes (7). The presence of these hydroxylated metabolites in the environment may impact the ecosystems in which they are generated since they are toxic to living organisms, including bacteria (8). Among their toxicological effects toward mammals, certain congeners are recognized endocrine disrup...

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Section: Resultssupporting

confidence: 81%

Metabolism of Doubly para -Substituted Hydroxychlorobiphenyls by Bacterial Biphenyl Dioxygenases

Pham

Sondossi

Sylvestre

2015

Appl Environ Microbiol

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“…Mechanisms involving reactive metabolites have been proposed in the initiating action of PCBs. Lower-chlorinated biphenyls can be metabolized by cytochrome P450 1A1, 1A2, 2B1/2B2, via arene oxides to mono-and dihydroxylated intermediates and further to quinones (5,6). Quinones are reactive electrophiles, which can readily undergo Michael addition with a multitude of intracellular nucleophiles, such as amino acids, glutathione (GSH), proteins, and nucleic acids.…”

mentioning

confidence: 99%

Nonenzymatic displacement of chlorine and formation of free radicals upon the reaction of glutathione with PCB quinones

Song

Wagner

Witmer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

133

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The reactions of glutathione (GSH) with polychlorinated biphenyl (PCB) quinones having different degrees of chlorination on the quinone ring were examined. EPR spectroscopy and MS revealed 2 types of reactions yielding different products: (i) a nonenzymatic, nucleophilic displacement of chlorine on the quinone ring yielding a glutathiylated conjugated quinone and (ii) Michael addition of GSH to the quinone, a 2-electron reduction, yielding a glutathiylated conjugated hydroquinone. The pKa of parent hydroquinone decreased by 1 unit as the degree of chlorination increased. This resulted in a corresponding increase in the oxidizability of these chlorinated hydroquinones. The reaction with oxygen appears to be first-order each in ionized hydroquinone and dioxygen, yielding hydrogen peroxide stoichiometrically. The generation of semiquinone radicals, superoxide, and hydroxyl radicals was observed by EPR; however, the mechanisms and yields vary depending on the degree of the chlorination of hydroquinone/quinone and the presence or absence of GSH. Our discovery that chlorinated quinones undergo a rapid, nonenzymatic dechlorination upon reaction with GSH opens a different view on mechanisms of metabolism and the toxicity of this class of compounds.dechlorination ͉ EPR ͉ superoxide ͉ semiquinone ͉ hydrogen peroxide P olychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants (1, 2). Many PCBs are poorly biodegradable and thus accumulate and are amplified through the food chain (3). Several congeners, including lower chlorinated PCBs, act as tumor promoters (4). Mechanisms involving reactive metabolites have been proposed in the initiating action of PCBs. Lower-chlorinated biphenyls can be metabolized by cytochrome P450 1A1, 1A2, 2B1/2B2, via arene oxides to mono-and dihydroxylated intermediates and further to quinones (5, 6). Quinones are reactive electrophiles, which can readily undergo Michael addition with a multitude of intracellular nucleophiles, such as amino acids, glutathione (GSH), proteins, and nucleic acids. Quinones can also be reduced to highly reactive semiquinone radicals, which in turn, lead to the formation of reactive oxygen species (ROS), causing oxidative stress and toxicity (7).GSH is the major nonprotein sulfhydryl in cells (8). As a nucleophile, it will conjugate with electrophiles both enzymatically and nonenzymatically; conjugation with various xenobiotics and/or their metabolic intermediates typically converts them into less toxic products. These reactions can be complex because of the possible involvement of a variety of free radicals (9, 10). Here, we evaluate the redox properties and mechanisms of the reactions of GSH with PCB quinones. We have discovered that certain chlorinated quinones not only undergo Michael addition reactions with GSH, but also GSH can nonenzymatically displace chlorine on the quinone ring. Results and DiscussionGlutathione can react with quinone rings via Michael addition forming corresponding hydroquinones (11, 12), Q ϩ GSH 3 GS-H 2 Q.[1]These hydroquinon...

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“…The first step in biotransformation by cytochromes P450 (CYPs) is the oxidation to an arene oxide with an epoxide group. Arene oxides can undergo further biotransformation to a mono-hydroxylated form and further to di-hydroxylated metabolites, which may be oxidized to quinones (McLean et al, 1996a). The arene oxide and quinone metabolites are electrophiles and can bind to nucleophilic sites in amino acids, proteins, and DNA (Amaro et al, 1996;Arif et al, 2003;McLean et al, 1996b;Pereg et al, 2002;Pereg et al, 2001;Srinivasan et al, 2001;Srinivasan et al, 2002;Tampal et al, 2003).…”

Section: Mutant Frequency and Mutations Caused By Pcb3 And 4-oh-pcb3mentioning

confidence: 99%

Mutagenicity of 3-methylcholanthrene, PCB3, and 4-OH-PCB3 in the lung of transgenic BigBlue® rats

Maddox

Wang

Kirby

et al. 2008

Environmental Toxicology and Pharmacology

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Recent findings of high levels of predominantly lower chlorinated biphenyls in indoor and outdoor air open the question of possible health consequences. Lower chlorinated biphenyls are more readily metabolized to reactive and potentially harmful intermediates, acting as mutagens and cancer initiators. The goal of this study was to assess the mutagenicity of PCB3 in the lungs of rats. Male BigBlue® 334 Fisher transgenic rats, which carry the bacterial lacI gene as a target of mutagenicity, were given intraperitoneal injections of corn oil, 3-methylcholanthrene (3-MC, positive control), 4-monochlorobiphenyl (PCB3) or its metabolite 4-hydroxy-PCB3 (4-OH-PCB3) weekly for 4 weeks. Lungs tissue was harvested to determine mutant frequencies, mutation spectra, and pathological changes. 3-MC caused a 15-fold increase in mutant frequency and an increase in transversion type mutations; a very early occurrence of this type of mutation in lung tissue was previously identified in Ki-ras oncogenes of lung tumors from 3-MC exposed mice. The 2-fold increase in the mutant frequency after treatment with PCB3 and 4-OH-PCB3 was not statistically significant, but a shift in the mutation spectra, especially with PCB3, and an increase in mutations outside of the hotspot region for spontaneous mutations (bp 1-400), suggest that PCB3 and possibly 4-OH-PCB3 are mutagenic in the rat lung.

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Identification of Catechol and Hydroquinone Metabolites of 4-Monochlorobiphenyl

Cited by 144 publications

References 36 publications

Metabolism of Doubly para -Substituted Hydroxychlorobiphenyls by Bacterial Biphenyl Dioxygenases

Metabolism of Doubly para -Substituted Hydroxychlorobiphenyls by Bacterial Biphenyl Dioxygenases

Nonenzymatic displacement of chlorine and formation of free radicals upon the reaction of glutathione with PCB quinones

Mutagenicity of 3-methylcholanthrene, PCB3, and 4-OH-PCB3 in the lung of transgenic BigBlue® rats

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