A Mathematical Model for Intra-cellular Effects of Toxins on DNA Adduction and Repair
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Authors
Gaver, D.P.
Jacobs, P.A.
Burkhart, J.G.
Carpenter, R.L.,
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1997
Date
1997
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Abstract
The processes by which certain classes of toxic compounds or their metabolites may react
with DNA to alter the genetic information contained in subsequent generations of cells or
organisms are a major component of hazard associated with exposure to chemicals in the
environment. Many classes of chemicals may form DNA adducts and there may or may not
be a defined mechanism to remove a particular adduct from DNA independent of replication.
Many compounds and metabolites that bind DNA also readily bind existing proteins;
some classes of toxins and DNA adducts have the capacity to inactivate a repair enzyme and
divert the repair process competitively. This paper formulates an intracellular dynamic
model for one aspect of the action of toxins that form DNA adducts, recognizing a capacity
for removal of those adducts by a repair enzyme combined with reaction of the toxin and/or
the DNA adduct to inactivate the repair enzyme. This particular model illustrates the
possible saturation of repair enzyme capacity by the toxin dosage and shows that bistable
behavior can occur, with the potential to induce abrupt shifts away from steady-state
equilibria. The model suggests that bistable behavior, dose and variation between individuals
or tissues may combine under certain conditions to amplify the biological effect of dose
observed as DNA adduction and its consequences as mutation. A model recognizing
stochastic phenomena also indicates that variation in within-cell toxin concentration may
promote jumps between stable equilibria.
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Article
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Bulletin of Mathematical Biology, 59, 1997, pp. 89-106.
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Operations Research (OR)
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Gaver, D.P. and Jacobs, P.A., Carpenter, R.L., and Burkhart, J.G.A Mathematical Model for Intra-cellular Effects of Toxins on DNA Adduction and RepairBulletin of Mathematical Biology, 59, 1997, pp. 89-106.
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defined in Title 17, United States Code, Section 101. Copyright protection is not available for this work in the United States.