Radiobiology 4

Molecular biology
IRRADIATION OF MACROMOLECULES
• When macromolecules are irradiated in solution in vitro, three major
effects occur: main-chain scission, cross-linking, and point lesions
• In vitro is irradiation outside of the cell or body. In vivo is irradiation
within the body
• When macromolecules are irradiated in vitro, that is, outside the body
or outside the cell, a considerable radiation dose is required to
produce a measurable effect
• Irradiation in vivo, that is, within the living cell, demonstrates that
macromolecules are considerably more radiosensitive in their natural
state
Main-Chain Scission
• Main-chain scission is the breakage of the backbone of the long-chain
macromolecule.
• The result is the reduction of a long, single molecule into many smaller
molecules, each of which may still be macromolecular.
• Main-chain scission reduces not only the size of the macromolecule but
also the viscosity of the solution.
• A viscous solution is one that is very thick and slow to flow, such as cold
maple syrup.
• Tap water, on the other hand, has low viscosity. Measurements of
viscosity determine the degree of main-chain scission
Cross-Linking
• Some macromolecules have small, spur-like side structures that
extend off the main chain. Others produce these spurs as a
consequence of irradiation
• These side structures can behave as though they had a sticky
substance on the end, and they attach to a neighboring
macromolecule or to another segment of the same molecule
• Radiation-induced molecular cross-linking increases the viscosity of a
macromolecular solution
Point Lesions
• Radiation interaction with macromolecules also can result in
disruption of single chemical bonds
• Point lesions are not detectable, but they can cause a minor
modification of the molecule, which in turn can cause it to
malfunction within the cell.
• Point lesions can result in the stochastic radiation effects observed at
the whole-body level
• all these types of radiation effects on macromolecules are reversible
through intracellular repair and recovery
Macromolecular Synthesis
• Catabolism - Molecular nutrients are brought to the cell and are
diffused through the cell membrane, where they are broken down
into smaller molecules with an accompanying release of energy
• Anabolism - the synthesis of macromolecules from smaller molecules.
The synthesis of proteins and nucleic acids is critical to the survival of
the cell and to its reproduction
• Metabolism consists of catabolism and anabolism
DNA is the most radiosensitive molecule
Radiation Effects on DNA
• DNA is the most important molecule in the human body because it
contains the genetic information for each cell
• Each cell has a nucleus that contains DNA complexed with other
molecules in the form of chromosomes
• Chromosomes therefore control the growth and development of the
cell; these in turn determine the characteristics of the individual
• If radiation damage to the DNA is severe enough, visible chromosome
aberrations may be detected
• Damage to the DNA also can result in abnormal metabolic activity.
• Uncontrolled rapid proliferation of cells is the principal characteristic
of radiation-induced malignant disease.
• That describes the cause of a stochastic effect.
• If damage to the DNA occurs within a germ cell, then it is possible
that the response to radiation exposure will not be observed until the
following generation or even later.
• This describes the cause of a genetic effect, which has all the
characteristics of a stochastic effect
• The DNA molecule can be damaged without the production of a
visible chromosome aberration.
• Although such damage is reversible, it can lead to cell death. If
enough cells of the same type respond similarly, then a particular
tissue or organ can be destroyed.
• That describes the cause of a deterministic effect
• Cell death, malignant disease, and genetic effects result from
irradiation of DNA
Radiolysis of Water
• irradiation of water represents the principal radiation interaction in
the body
• When water is irradiated, it dissociates into other molecular products;
this action is called radiolysis of water
• it is ionized and dissociates into two ions
• After this initial ionization, a number of reactions can happen.
• First, the ion pair may rejoin a stable water molecule. In this case, no
damage occurs.
• Second, if these ions do not rejoin, it is possible for the negative ion
(the electron) to attach to another water molecule through the
following reaction to produce yet a third type of ion
• The HOH+ and HOH− ions are relatively unstable and can dissociate
into still smaller molecules as follow
• The final result of the radiolysis of water is the formation of an ion
pair, H+ and OH− , and two free radicals, H* and OH*
• The ions can recombine; therefore, no biologic damage would occur.
• These types of ions are not unusual.
• Many molecules in aqueous solution exist in a loosely ionized state
because of their structure.
• Salt (NaCl), for instance, easily dissociates into Na+ and Cl− ions. Even
in the absence of radiation, water can dissociate into H+ and OH− ions
• A free radical is an uncharged molecule that contains a single unpaired electron in
the outer shell
• They are highly reactive
• Free radicals are unstable and therefore exist with a lifetime of less than 1 ms
• they are capable of diffusion through the cell and interaction at a distant site
• Free radicals contain excess energy that can be transferred to other molecules to
disrupt bonds and produce point lesions at some distance from the initial ionizing
event
• The H* and OH* molecules are not the only free radicals that are produced during
the radiolysis of water
• The OH* free radical can join with a similar molecule to form hydrogen peroxide
• Hydrogen peroxide is poisonous to the cell and therefore acts as a
toxic agent
• The H* free radical can interact with molecular oxygen to form the
hydroperoxyl radical as follows
• The hydroperoxyl radical, along with hydrogen peroxide, is considered
to be the principal damaging product after the radiolysis of water.
• Hydrogen peroxide also can be formed by the interaction of two
hydroperoxyl radicals as follows
DIRECT AND INDIRECT EFFECTS
• When the ionizing event occurs on the target molecule, the effect of
radiation is direct
• if the initial ionizing event occurs on a distant, noncritical molecule,
which then transfers the energy of ionization to the target molecule, an
indirect effect has occurred
• because the human body consists of approximately 80% water and less
than 1% DNA, it is concluded that essentially all of the effects of
irradiation in vivo result from indirect effect
• When oxygen is present, as in living tissue, the indirect effects are
amplified because of the additional types of free radicals that are formed
• Free radicals, with their excess energy of reaction, are the
intermediate molecules
• They migrate to the target molecule and transfer their energy, which
results in damage to that target molecule
• The principal effect of radiation on humans is indirect.