BIOLOGICAL EFFECTS OF IONIZING RADIATION AT MOLECULES AND CELLS

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BIOLOGICAL EFFECTS OF IONIZING RADIATION AT
MOLECULES AND CELLS
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The stage of action of ionizing radiation
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Effect of radiation on atom and molecules
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Effects of ionizing radiation at atomic level
Ionization
Excitation
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Mechananisms of damage at molecular level
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Direct action of ionizing radiation
Ionizing radiation RH R- H
Bond breaks
?
?
O II R C NH2 amide (ketol)
Tautomeric shifts
OH I R C NH imidol (enol)
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Indirect action of ionizing radiation
OH-
H
e-
O
H
X ray ? ray
H
Ho
P
OHo
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Radiolysis of H2O molecule
Shared electron
Shared electron
H-O-H ? H OH- (ionization) H-O-H ? H0
OH0 (free radicals)
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Reaction of H2O molecule radiolysis
?2? h? ? ?2? ?- ?2? h? ? ?2? ? ??
??? ?2? ?- ? ?-???? ? ?? ??- ?2? ?- ? ?2?
? ?? ??? ?2? ? ? ??? ?- ? ? ?? ?2? ??-
? ?2? ??? ?2? ?2? ? ?3? ??? ?3? ?- ?
?2? ??
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Effects of oxygen on free radical formation
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)
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Reactions with free radicals
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
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Lifetimes of free radicals
HO2o
RO2o
Ho
OHo
3nm
OHo
Ho
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
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Relation between linear energy transfer (LET) and
type of action

• Direct action is predominant with high LET
  radiation, e.g. alpha particles and neutrons
• Indirect action is predominant with low LET
  radiation, e.g. X and gamma rays

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Effect of radiation on biological molecules
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Biochemical reactions with ionizing radiation

• DNA is primary target for cell damage from
  ionizing radiation

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Radiation induced DNA damage
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The most important types of radiation induced
lesions in DNA
Base damage 1000-2000 per 1 Gy
Single-strand breaks 500-1000 per 1 Gy
Double strand breaks 40-50 per 1 Gy
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Mechanisms of base excision and nucleotide
excision repair
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Mechanism of single-strand breaks DNA repair

Exonuclease
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DNA restoration failure
Unrejoined DNA double strand breaks
Incorrect repair of DNA damage
Cytotoxic effect
Mutations
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Radiation induced membrane damage
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Effect of radiation on cells
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Types of cellular damage
Norma
Mutation
repair
Changes of metabolism function
Interphase cell death
Mitotic cell death
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Cell cycle
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Radiosensitivity of cell in cell cycle
M G1 S
G2 M
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
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Mitotic death
NORMAL
IRRADIATED
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Bergonié and Tribondeaus law (1906)

• The most radiosensitive cells are
• actively proliferating (dividing) at the time of
  exposure
• undifferentiated (non-specialized in structure
  and function)

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Interphase death
Why are peripheral blood lymphocytes highly
sensitive to radiation, although well
differentiated?
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Morphological forms of cell death

• 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

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Changes of cell metabolism and function

• 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.

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Radiation induced chromosome damage
Chromosomes
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Radiation induced chromosomal aberrations
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Relative cellular radiosensitivity

• 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.

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Summary of lection

• Cells going through the division phase (M and S)
  are generally the most sensitive to ionizing
  radiation. Exceptions lymphocytes and some bone
  marrow stem cells, which exhibit interphase death
  
• Bone marrow consists of progenitor and stem
  cells, the most radiosensitive cells in the human
  body and the most important in controlling
  infection

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Lecture is ended
THANKS FOR ATTENTION
In lecture materials of the International Atomic
Energy Agency (IAEA), kindly given by doctor
Elena Buglova, were used