Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Copper
671
Tocopherol
Mitochondrial electron transport
O 2
A
Reduced substrates Cytochrome system H 2 O
O 2 . -
MnSOD
H 2 O 2 1/2 O 2 H 2 O 2
Catalase
Tocopherol
SOD Catalase
B
2H Cu(II)
Fe(II)
O 2 O 2 •-
H 2 O 2
H 2 O
• OH HO-
O 2
H 2 O
Fe 2 or Cu 1
D
NADH/NADPH oxidase
Xanthine oxidase
Lipoxygenase
Cycloxygenase
P-450 monooxygenase
Mitochondrial oxidative-
Phosphorylation
Electron transport
NO•
Fenton reaction
ONOO- •OH OH-
• OH HO-
Metal
Chaperones
Metal Complexes
(e.g. MT, Ferritin)
"RH" "RH" "RH"
Organic and Lipid peroxides (ROOH)
Glutathione Peroxidase
GSH
ROH H 2 O
Glutathione
Reductase
NADP
Hexode
GSSG C
Monophosphate
Shunt
NADPH
Tocopherol
FIGURE 22-3 Major sources and regulation of reactive oxidant species (ROSs) in cells. Depending on the stage of development and condition, on a
per mole basis ROSs are normally generated at rates of 1% to 4% of the oxygen consumed or greater when ROS regulation is disrupted. A major source
of ROS is derived from superoxide anion (O 2 ) generated in the mitochondrion (A) because of uncoupling from the cytochrome oxidase system during
mitochondrial electron transport. In addition to water and oxidized metabolites as products, superoxide anion and H 2 O 2 are produced. Enzymes, such as
catalase and MnSOD (localized in the mitochondria) control excess production of O 2
and H 2 O 2 . When there is subsequent leakage from mitochondria,
an increase in the cellular pool of ROS occurs owing both to ROSs from mitochondria and production from other organelles and cytosol (B). Sources
of ROSs from other organelles and cytosol are the products from reactions catalyzed by NADH and NAPH oxidases, xanthine oxidase (activated during
ischemic injury), lipoxygenase, and P450 monooxygenase enzymes (localized mainly in the smooth endoplasmic reticulum and responsible for the
metabolism of xenobiotics, drugs, and secondary metabolites). In addition, excess ROS can potentially alter nitric oxide metabolism (e.g., formation of
peroxynitrites) and cause the generation of organic and lipid peroxides and so-called Fenton products (C). For example, “ RH, ” used to depict numerous
aromatic and lipid-derived possibilities as potential reactants, can be converted to ROOH, potential organic peroxide-containing products. Excess superoxide
anion, ROOH, OH-, OH · , and other ROSs can then damage proteins, nucleic acids, and lipids, particularly lipid structures in cell and organelle
membranes. Important to this discussion, metals can act as both catalysts for ROS formation and cofactors for antioxidant enzymes that modulate influence
ROS metabolism. For example, (1) MnSOD and CuZn SOD (superoxide dismutases) cause the dismutation of excess superoxide anion to peroxide,
(2) catalase (contains Fe) and glutathione peroxidase (contains Se) can control excess of both hydrogen and organic peroxides. As an additional defense,
metal chaperones (see text), metallothionein (MT), or ferritin control “ free ” metal ion concentrations in cells that are capable of redox (D). Redox metals
(Fe or Cu) can act as Fenton catalysts and promote the homolytic cleavage of H 2 O 2 to OH · and OH-, which are highly damaging oxidants. Reduction
in the concentration or sequestration of metals (depicted by the dashed line) markedly reduces potential Fenton products. As a final line of defense,
tocopherols and polyphenolic and related phytochemicals, which localize to lipid membranes, provide additional ROS defense.