Biomedical Engineering Reference
In-Depth Information
Fig. 6.2 Reactive oxygen species produced by copper-mediated catalysis
Fig. 6.3 Copper-mediated sulfhydryl group depletion
Copper-induced toxicity can be very diverse depending on the environment
surrounding this metal, generating damage by multiple mechanisms. Therefore,
measuring copper toxicity in vivo can be a challenge. One of the most important
modes of toxicity is based on the redox properties of copper, where under aerobic
conditions copper can alternate oxidation state and exchange electrons with accep-
tor or donor groups, such as oxygen and sulfur residues. Copper can exert its
toxicity by reacting directly with biomolecules or indirectly through activation of
oxygen species.
In case of indirect toxicity, copper catalyzes production of reactive oxygen
species (ROS) via Fenton-like Haber-Weiss reactions (Fig. 6.2 )[ 49 ]. ROS, per se
are extremely reactive when formed and quickly cause damage to the surrounding
biomolecules: lipids, proteins and DNA [ 95 ].
The low constant rate of hydrogen peroxide reaction with superoxide, as
described in the equation 1 (Fig. 6.2 ), is greatly enhanced by presence of copper
ions. During one cycle cupric ion is first reduced to cuprous ion by superoxide anion
(Fig. 6.2 , equation 2), then Cu(II) is oxidized back to Cu(I) by hydrogen peroxide
(Fig. 6.2 , equation 3), and the cycle repeats itself producing more hydroxyl radicals
that induce cell damage. Additionally, in the low valence state Cu(I) can form
active complexes with oxygen capable of attacking surrounding molecules. These
types of reactions will be further discussed in the membrane damage section
(or lipid oxidation chemistry).
Direct copper toxicity to biomolecules has been linked to the depletion of
sulfhydryl groups (Fig. 6.3 ), where copper reacts with glutathione (GSH) producing
glutathione disulfide (GSSG) or with the amino-acid cysteine generating cystine
groups (Fig. 6.3 , equation 4).
Cuprous ions generated by sulfhydryl group oxidation are recycled back to
cupric ion producing hydrogen peroxide. This hydrogen peroxide can be converted
to the more highly reactive ROS, hydroxyl radical and superoxide, by the equations
2 and 3 described above [ 50 ].
Damage to nucleic acids, lipids, and proteins by previously described mecha-
nisms has been demonstrated in vitro in many studies (e.g. [ 4 , 7 , 11 , 18 , 42 , 45 , 95 ]).
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