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EXOGENOUS OXIDANTS
May come from several sources such as :
Pollutants
Drugs
Food additives
Chemicals used in industry
etc
OXIDANTS & FREE RADICALS (1)
Oxidants are electron acceptors
Example: Fe+++
Fe 3+ + e- Fe 2+
H : 0 : H ( H – 0 – H ) .H + .OH
3. Free radicals are all oxidants but not all oxidants are
free radicals.
Example :
Hydrogen peroxide (H2O2): oxidant, non radical
Hydoxyl radical (.OH) : oxidant, radical
FREE RADICALS CAN TRIGGER
CHAIN REACTIONS
1. When a free radical react with a nonradical the result will
be the formation of a new radical:
R1. + R2 – H R1 – H + R2.
O2 + 4 H+ + 4e- 2 H2O
H2O2 1
O2
Fe /CU
++ +
O2 .OOH .OH
+
Fe+ /
++ CU
+
/CU Fe
+
O2.- & H2O2 are primary ROS from which all the
others are derived
FORMATION OF PRIMARY R.O.S.
H2 O 2
OXIDASES (ENDOPLAS MIC RETICULUM, PEROXISOME)
RH2 + O2 R + H 2O 2
H2 O 2 :
BY PRODUCTS OF :
1. NORMAL PROCESSES OXIDATIVE PHOSPHORYLATION
2. HEMOGLOBIN OXYGENATION (FORMATION OF Hb O2)
3. Hydroxylation by E.Monoaxygenation (sit.P450 dan sit b4)
XANTHINE OXIDASE
Tak ada pada sel mamalia
Terbentuk dari xantin dehidrogenase
dalam keadaan hipoksia / iskhemia
XD XO + peptida
Reaksi ini tak reversibel sehingga jika pasokan
oksigen menjadi normal dapat terbentuk ion
superoksid yang dapat merusak jaringan (re
perfusion injur
ION SUPEROKSID
Sebenarnya tak terlalu reaktif
•O2¯ + H+ .OOH (radikal peroksil yg reaktif)
.OOH + XH .X + H2O2
Ion superoksid berbahaya jika ada bersama dg
H2O2 (reaksi Haber Weiss)
•O2¯ + H2O2 O2 + OH- + .OH
Radikal hidroksil :
berbahaya karena paling reaktif
Bukan produk primer proses biologi
Berasal dari H2O2 dan •O2¯
FORMATION OF OTHER R.O.S.
•OOH
•O2¯ + H+ •OOH
•OH
•O2¯ + H2O2 Fe+ + +
O2 + OH¯ + •OH
(Cu++ ) HABER-WEISS REACTION
O2 1
H2O2 + ClO¯ (MYELOPEROXIDASE) H2O + Cl¯ + O2
EFFECT OF ROS
1. ROS can react with many substances either simple
compounds such as amino acids, fatty acids,
cholesterol etc or more complex substances such as
DNA & proteins
Lipid radical
b. Propagation
L. + O2 LOO.
Peroxylipid radical
LH + LOO. L. + LOOH
Lipid peroxide
c. Termination
L. + L. L – L
3. LOOH undergo further reactions leading to clevage of the F.A. chain
4. Termination causes cross-linking between 2 FA Chain
EFFECT OF ROS ON MEMBRANE LIPIDS
EFFECT OF ROS ON DNA(1)
EFFECT OF ROS ON DNA(2)
EFFECT OF ROS ON DNA(3)
EFFECT OF ROS ON PROTEINS
ANTIOXIDANTS (1)
1. In its original definition in chemistry antioxidants
are electron donors
Example: Cu + Cu2+ + e-
2. In Biology (and Medicine) however, antioxidants
have a much broader meaning, it is:
any substance that prevent the formation or
activity of oxidants
3. This broader definition in Biology includes not only
electron donors but other sustances such as :
• Metal binding proteins
• Enzymes
ANTIOXIDANTS (2)
ANTIOXIDANTS CAN BE CLASSIFIED ACCORDING :
A. Its mode of action
1. Preventive antioxidants prevent undue accumulation of oxidants
2. Chain breaking antioxidants prevent propagation of chain reactions
initiated by free radicals
B. Its solubility
1. Lipophilic antioxidants
Hydrophobic, fat solluble molecules, act in cell membranes :
Tocopherols (vitamin E)
carotene (provitamin A)
2. Hydrophilic antioxidants
Hydrophilic, water solluble molecules act in cytosol and E.C.F.:
Ascorbic acid (vitamin C)
Glutathione
Cysteine
Others (e.g.: uric acid)
PREVENTIVE ANTIOXIDANTS
Preventive antioxidants prevents accumulation of: O 2, H2O2 and
Transition metal ions Fe2+ and Cu+
1. O2.- & H2O2 are primary ROS from which all others ROS are
derived Thus preventing the accumulation of O 2. and H2O2
will prevent accumulation of all the other ROS
2O2.- + 2 H+ O2 + H2O2
L. + TocH LH + Toc.
(Tocopheryl radical)
5. Alternatively, Toc. Can also react with cysteine (Cys SH) or glutathione
(GSH), generating cystine (Cys SS Cys) or oxidised glutathione (GSSG)
6. Tocopherols can only react at a relatively high PO 2. At low PO2, the role
of tocopherols is replaced by R-carotene, whose radical ( -carotenyl
radical) is also relatively stable due to electron delocalisation