Quinones & Semiquinone Radical from PCBs
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(possibly from seafood, meat, milk, etc) and are also deficient in
functional NQO1 enzyme. NQO1 detoxifies quinones. Tyrosinase, which
increases conversion of PCBs to radicals, is present in skin pigment
cells and some nerves.
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Semiquinone Radicals from Oxygenated Polychlorinated Biphenyls:
Electron Paramagnetic Resonance Studies.
Polychlorinated biphenyls (PCBs) can be oxygenated to form very
reactive hydroquinone and quinone products. A guiding hypothesis in
the PCB research community is that some of the detrimental health
effects of some PCBs are a consequence of these oxygenated forms
undergoing one-electron oxidation or reduction, generating semiquinone
radicals (SQ (*-)). These radicals can enter into a futile redox cycle
resulting in the formation of reactive oxygen species, that is,
superoxide and hydrogen peroxide. Here, we examine some of the
properties and chemistry of these semiquinone free radicals. Using
electron paramagnetic resonance (EPR) to detect SQ (*-) formation, we
observed that (i) xanthine oxidase can reduce quinone PCBs to the
corresponding SQ (*-); (ii) the heme-containing peroxidases
(horseradish and lactoperoxidase) can oxidize hydroquinone PCBs to the
corresponding SQ (*-); (iii) tyrosinase acting on PCB ortho-
hydroquinones leads to the formation of SQ (*-); (iv) mixtures of PCB
quinone and hydroquinone form SQ (*-) via a comproportionation
reaction; (v) SQ (*-) are formed when hydroquinone-PCBs undergo
autoxidation in high pH buffer ( approximately >pH 8); and,
surprisingly, (vi) quinone-PCBs in high pH buffer can also form SQ
(*-); (vii) these observations along with EPR suggest that hydroxide
anion can add to the quinone ring; (viii) H 2O 2 in basic solution
reacts rapidly with PCB-quinones; and (ix) at near-neutral pH SOD can
catalyze the oxidization of PCB-hydroquinone to quinone, yielding H 2O
2. However, using 5,5-dimethylpyrroline-1-oxide (DMPO) as a spin-
trapping agent, we did not trap superoxide, indicating that generation
of superoxide from SQ (*-) is not kinetically favorable. These
observations demonstrate multiple routes for the formation of SQ (*-)
from PCB-quinones and hydroquinones. Our data also point to futile
redox cycling as being one mechanism by which oxygenated PCBs can lead
to the formation of reactive oxygen species, but this is most
efficient in the presence of SOD.
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Chlorination Increases the Persistence of Semiquinone Free Radicals
Derived from Polychlorinated Biphenyl Hydroquinones and Quinones.
Polychlorinated biphenyls (PCBs) comprise a group of persistent
organic pollutants that differ significantly in their physicochemical
properties, their persistence, and their biological activities. They
can be metabolized via hydroxylated and dihydroxylated metabolites to
PCB quinone intermediates. We have recently demonstrated that both
dihydroxy PCBs and PCB quinones can form semiquinone radicals (SQ
(*-)) in vitro. These semiquinone radicals are reactive intermediates
that have been implicated in the toxicity of lower chlorinated PCB
congeners. Here we describe the synthesis of selected PCB metabolites
with differing degrees of chlorination on the oxygenated phenyl ring,
e.g., 4,4'-dichloro-biphenyl-2,5-diol, 3,6,4'-trichloro-biphenyl-2,5-
diol, 3,4,6,-trichloro-biphenyl-2,5-diol, and their corresponding
quinones. In addition, two chlorinated o-hydroquinones were prepared,
6-chloro-biphenyl-3,4-diol and 6,4'-dichloro-biphenyl-3,4-diol. These
PCB (hydro-)quinones readily react with oxygen or via
comproportionation to yield the corresponding semiquinone free
radicals, as detected by electron paramagnetic resonance spectroscopy
(EPR alias ESR). The greater the number of chlorines on the (hydro-)
quinone (oxygenated) ring, the higher the steady-state level of the
resulting semiquinone radical at near neutral pH.
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Sulfhydryl binding and topoisomerase inhibition by PCB metabolites.
Polychlorinated biphenyls (PCBs) are highly persistent contaminants in
our environment. Their persistence is due to a general resistance to
metabolic attack. Lower halogenated PCBs, however, are metabolized to
mono- and dihydroxy compounds, and the latter may be further oxidized
to quinones with the formation of reactive oxygen species (ROS). We
have shown that PCB metabolism generates ROS in vitro and in cells in
culture and this leads to oxidative DNA damage, like DNA strand breaks
and 8-oxo-dG formation. In the present study, we have evaluated the
reactivity of PCB metabolites with other nucleophiles, like
glutathione (GSH), by assessing (1) quantitative GSH binding in vitro,
(2) GSH and thiol (sulfhydryl) depletion in HL-60 cells, (3) the
associated cytotoxicity, and (4) the inhibition of topoisomerase II
activity in vitro. PCB quinones were found to bind GSH in vitro at a
ratio of 1:1.5 and to deplete GSH in HL-60 cells as measured by both
spectrophotometric and spectrofluorometric methods. By flow cytometry
analysis, we confirmed that there was intracellular GSH depletion in
HL-60 cells by PCB quinones and this is associated with cytotoxicity.
On the other hand, the PCB hydroquinone metabolites did not bind GSH
or other thiols within 1 h of exposure. However, by spectral analyses
we found that the PCB hydroquinones could be oxidized enzymatically to
the quinones, which could then bind GSH. The resulting hydroquinone-
glutathione addition product(s) could undergo a second and third cycle
of oxidation and GSH addition with the formation of di- and tri-GSH-
PCB adducts. The effect of the PCB metabolites was also tested on a
sulfhydryl-containing enzyme, topoisomerase II. PCB quinones inhibited
topoisomerase II activity while the PCB hydroquinone metabolites did
not. Hence, the oxidation of PCB hydroquinone metabolites to quinones
in cells followed by the binding of quinones to GSH and to protein
sulfhydryl groups and the resulting oxidative stress may be important
aspects of the toxicity of these compounds.
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Environmental contaminants and redox status of coenzyme Q10 and
vitamin E in Inuit from Nunavik.
The Inuit are heavily exposed to potentially prooxidant contaminants
such as methylmercury (MeHg) and polychlorinated biphenyls (PCB)
through their traditional diet. This diet is also an abundant source
of n-3 polyunsaturated fatty acids (n-3 PUFA), selenium, and
antioxidants, which might reduce cardiovascular risk. Although Inuit
from Nunavik have low concentrations of plasma oxidized low-density
lipoprotein (OxLDL) and elevated glutathione-related antioxidant
defenses, the variance in OxLDL was predicted by PCB and blood
glutathione, leaving the issue of contaminant-associated oxidative
stress unresolved. The objective of the study was to assess oxidative
stress in these Inuit by measuring the plasma concentrations and redox
states of alpha-tocopherol and coenzyme Q10 (CoQ10), 2 sensitive
biomarkers of oxidative stress, in relation to exposure. Plasma
lipophilic antioxidants were determined by high-performance liquid
chromatography-coupled electrochemical detection; and their relations
to PCB, MeHg, n-3 PUFA, selenium, and OxLDL were assessed by
multivariate analyses. Ubiquinol-10, ubiquinone-10, and ubiquinone-10
to CoQ10(total) ratio were elevated as compared with white populations
but showed no associations with PCB, MeHg, or n-3 PUFA. Ubiquinol-10
(beta = .23, P = .007) and CoQ10(total) (beta = .27, P = .009) were
predicted by blood selenium; and alpha-tocopherol, by PCB (beta =
4.12, P = .0002), n-3 PUFA (beta = 9.16, P = .02), and OxLDL (beta =
3.04, P = .05). Unexpectedly, the alpha-tocopheryl quinone to alpha-
tocopherol ratio, in the reference range, was negatively predicted by
PCB (beta = -0.41, P = .02). Using sensitive biomarkers of redox
alterations, we found no evidence for MeHg- or PCB-associated
oxidative stress in these Inuit. However, despite robust blood
antioxidant defenses, the unusually elevated ubiquinone-10 to CoQ10
(total) ratio (0.21 +/- 0.11) suggests some form of oxidative stress
of unknown origin.
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Above studies from:
http://www.freeradicalscience.com/showcitationlist.php?keyword=polychlorinated%20biphenyl%20pcb%20quinones