BIOLOGICAL EFFECTS OF IONIZING RADIATION AT MOLECULES AND CELLS.
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Transcript of BIOLOGICAL EFFECTS OF IONIZING RADIATION AT MOLECULES AND CELLS.
BIOLOGICAL EFFECTS BIOLOGICAL EFFECTS
OF IONIZING RADIATIONOF IONIZING RADIATION
AT MOLECULAT MOLECULES ES AND AND CCELLELLSS
The stage of action The stage of action of ionizing radiationof ionizing radiation
Physical stagePhysical stage The transfer of kinetic energy from The transfer of kinetic energy from ionizing radiation to atoms or molecules ionizing radiation to atoms or molecules leads to excitation and ionization of leads to excitation and ionization of these atoms or moleculesthese atoms or molecules
10 10 –– 1616 ––
10 10 – 15– 15 secondsseconds
Physic-chemical Physic-chemical stagestage
The displace of absorbed energy of The displace of absorbed energy of ionizing radiation into molecules and ionizing radiation into molecules and between them. Formation of free between them. Formation of free radicalsradicals
10 10 – 14– 14 – –
10 10 – 11– 11 secondsseconds
Chemical stageChemical stage Reactions between free radicals, Reactions between free radicals, reactions between free radicals and reactions between free radicals and intact molecules. Formation of molecules intact molecules. Formation of molecules with abnormal structure and functionwith abnormal structure and function
10 10 – 6– 6 – –
10 10 – 3– 3 secondsseconds
Biological stageBiological stage Formation of injures on all levels – from Formation of injures on all levels – from cellular structures to organism and cellular structures to organism and population. population. Development of processes of biological Development of processes of biological damage and reparative processes damage and reparative processes
Seconds Seconds
– – yearsyears
Effect of Effect of rradiation adiation on on atom and moleculesatom and molecules
Effects of Effects of ionizing ionizing rradiation adiation at at aatomic tomic llevelevel
IonizationExcitation
Mechananisms Mechananisms of of ddamageamage at molecular levelat molecular level
Direct Direct aactionction of ionizing radiationof ionizing radiation
Ionizing radiation + RH R- + H+
OH IR – C = NHimidol (enol)
O IIR – C = NH2
amide (ketol)
Tautomeric shifts
Bond breaks
e-
X ray ray P+
OH
H OH-
H+
Ho
OHo
Indirect Indirect aactionction of ionizing radiationof ionizing radiation
Radiolysis of HRadiolysis of H22O O mmoleculeolecule
Shared electron
Shared electron
H-O-H H+ + OH- (ionization)
H-O-H H0 + OH0 (free radicals)
Reaction of Reaction of HH22O O mmoleculeolecule rradiolysisadiolysis
Н2О + h Н2О+ + е-
Н2О + h Н2О* Но + НОо
Н2О + е- е-гидр Но + НО-
Н2О + е- Н2О* Но + ОНо
Н2О Н+ + ОНо
е- + Н+ Но
Н2О+ + ОН- Н2О + ОНо
Н2О+ + Н2О Н3О
+ + ОНо
Н3О+ + е- Н2О + Но
Effects of Effects of ooxygen xygen on on ffree ree rradical adical fformationormation
Oxygen can modify the reaction by enabling creation of other free radical species with greater stability and longer lifetimes
H0 + O2 HO20 (hydroperoxy free radical)
R0 + O2 RO20 (organic peroxy free radical)
Reactions with Reactions with ffree ree rradicalsadicals
H0 + OH0 H2O
H0 + H0 H2
OH0 + OH0 H2O2
RH + OH0 R0 + H2O
RH + H0 R0 + H2
R0 + OH ROH
R0 + H RH
R0 + O2 ROO0
ROO0 + RH ROOH + R0
Lifetimes of Lifetimes of ffree ree rradicalsadicals
3nm
Because short life of simple free radicals (10-10sec), only those formed in water column of 2-3 nm around DNA are able to participate in indirect effect
Ho
OHo Ho
OHo
HO2o RO2
o
Relation Relation bbetween etween llinear inear eenergy nergy ttransfer (LET) and ransfer (LET) and ttypeype of of aactionction
Direct actionDirect action is predominant with is predominant with high LET radiation,high LET radiation, e.g.e.g. alpha alpha particles and neutronsparticles and neutrons
Indirect actionIndirect action is predominant is predominant with with low LET radiationlow LET radiation,, e.g. e.g. X X and gamma raysand gamma rays
Effect of Effect of rradiation adiation on on biological biological moleculesmolecules
Biochemical Biochemical rreactions eactions with ionizing with ionizing radiationradiation
DNADNA is is primary targetprimary target for cell for cell damagedamage from ionizing radiatio from ionizing radiationn
Radiation induced Radiation induced DNA DNA ddamageamage
The most important types of The most important types of radiation induced lesions in radiation induced lesions in DNADNA
Single-strand breaks500-1000 per 1 Gy
Double strand breaks40-50 per 1 Gy
Base damage: 1000-2000 per 1 Gy
Mechanisms of Mechanisms of base base excision and nucleotide excision and nucleotide excision excision rrepairepair
Mechanism of Mechanism of ssingle-strand breaks DNA DNA rrepairepair
1
Endonuclease
2
DNA polymerase
4
DNA ligase
5
3 Exonuclease
DNA DNA rrestoration estoration ffailureailure
Unrejoined DNAdouble strand breaks
Incorrect repair of DNA damage
Cytotoxic effect Mutations
Radiation induced Radiation induced membrane damagemembrane damage
Effect of Effect of rradiation adiation on on ccellellss
Types of Types of ccellular ellular ddamageamage
Interphase cell death
Changes ofmetabolism& function
Mitotic cell death
Norma
repair
Mutation
Cell cycleCell cycle
Radiosensitivity of Radiosensitivity of ccell ell in in ccell ell ccycleycle
Relative survivability of cells irradiated in different phases of
the cell cycle: synchronised cells in late G2 and in mitosis (M)
showed greatest sensitivity to cell killing
M G1 S G2 M
NORMAL IRRADIATED
Mitotic Mitotic ddeatheath
The most ‘radiosensitive’ cells are actively proliferating (dividing) at
the time of exposure
undifferentiated (non-specialized in structure and function)
Bergonié and Tribondeaus’ Bergonié and Tribondeaus’ ‘law’ (1906)‘law’ (1906)
Interphase deathInterphase death
Why are peripheral blood lymphocytes highly sensitive to radiation, although well differentiated?
Pyknosis: The nucleus becomes contracted, spheroidal, and filled with condensed chromatin.
Karyolysis: The nucleus swells and loses its chromatin.
Protoplasmic Coagulation: Irreversible gelatin formation occurs in both the cytoplasm and nucleus.
Karyorrhexis: The nucleus becomes fragmented and scattered throughout the cell.
Cytolysis: Cells swell until they burst and then slowly disappear.
Apoptosis: Programmed cell death, usually be fragmentation
Morphological forms Morphological forms of cell deathof cell death
Block of Mitotic Cycle: Mitosis may be delayed or inhibited following radiation exposure.
Disruptions in Cell Growth: Cell growth may also be retarded, usually after a latent period.
Permeability Changes: Irradiated cells may show both increased and decreased permeability.
Changes in Cell Motility: The motility of a
cell may be decreased following irradiation.
Changes of cell Changes of cell metabolism and functionmetabolism and function
Radiation induced Radiation induced chromosome damagechromosome damage
ChromosomesChromosomes
Radiation Radiation iinduced nduced cchromosomal hromosomal aaberrationsberrations
Vegetative Cells: these cells, comprising differentiated functional cells of a large variety of tissues, are generally the most radiosensitive.
Differentiating Cells: these cells are somewhat less sensitive to radiation; they are relatively short‑lived and include the first generation produced by division of the vegetative mitotic cells.
Totally Differentiated Cells: these cells are relatively radioresistant; they normally have relatively long lifespans and do not undergo regular or periodic division in the adult stage, except under abnormal conditions such as following damage to or destruction of a large number of their own kind.
Fixed Nonreplicating Cells: these cells are most
radioresistant; they are highly differentiated morphologically and highly specialized in function.
Relative cellular radiosensitivity
Summary of lectionSummary of lection
• Cells going through the division phase (M Cells going through the division phase (M and S) are generally the most sensitive and S) are generally the most sensitive to ionizing radiation. to ionizing radiation. Exceptions: Exceptions: lymphocytes and some bone marrow stem cells, lymphocytes and some bone marrow stem cells,
which exhibit interphase deathwhich exhibit interphase death • Bone marrow consists of progenitor and Bone marrow consists of progenitor and
stem cells, the most radiosensitive cells stem cells, the most radiosensitive cells in the human body and the most in the human body and the most important in controlling infection important in controlling infection
Lecture is endedLecture is ended
THANKS FOR ATTENTION
In lecture materials of the International Atomic Energy Agency (IAEA), kindly given by doctor Elena Buglova, were used