| D. MECHANISM OF ADAPTATION'
involves RESPONSES ACTING TO PRESERVE OR REGAIN THE BIOLOGICAL HOMEOSTASIS in the face of increased harm from a NOXIOUS STIMULUS. | Adaptation |
| D. MECHANISM OF ADAPTATION
Adaptation of toxicity may result
from biological changes causing: | 1 Diminished delivery of the toxicant
to the target
2 Decreased size or susceptibility of the target
3 Increased capacity of the organism to repair itself
4 Strengthened mechanisms to compensate the toxicant inflicted dysfunction. |
| E. WHEN REPAIR FAILS
1 __ when the damage becomes too much; repair mechanisms are unable to repair the injury as when necessary enzymes or cofactors are consumed
2 Some types of toxic injuries cannot
be repaired effectively, as occurs
when xenobiotics are __
3 repair contributes to toxicity: | .
1 Repair fails
2 Covalently bound to proteins
3)
1 Excessive amounts of NAD+ are cleaved by PARP,
2 Too much NAD(P)H is consumed for the
repair of oxidized proteins and endogenous reductants |
| F. TOXICITY RESULTING FROM DYSREPAIR
1 Some toxicities involve dysrepair at
an __, such as a specific enzyme or process, or at different levels, such as tissue necrosis, fibrosis, and chemical carcinogenesis. | .
1 isolated level |
| F. TOXICITY RESULTING FROM DYSREPAIR
1) Tissue Necrosis
1 Cell injury progresses toward __ if molecular repair
mechanisms are inefficient or the molecular damage is not readily reversible.
2 Progression of cell injury to tissue necrosis can be intercepted by two repair mechanisms working in
concert:
3 Injured cells can initiate __ which counteracts the progression of the toxic injury by preventing necrosis of injured cells | .
1 cell necrosis
2 Apoptosis and
Cell proliferation.
3 apoptosis |
| F. TOXICITY RESULTING FROM DYSREPAIR
1) Tissue Necrosis
1 Repair process that can HALT THE PROPAGATION OF TOXIC INJURY
Initiated soon after cellular injury
This early cell division is thought to be INSTRUMENTAL IN THE RAPID AND COMPLETE RESTORATION of the injured tissue and the prevention of necrosis. | .
1 Proliferation of cells adjacent to the injured cells. |
| F. TOXICITY RESULTING FROM DYSREPAIR
1) Tissue Necrosis
1 an IMPORTANT DETERMINANT of the dose–response relationship for toxicants that cause tissue necrosis.
2 Tissue necrosis is caused by a certain dose of a toxicant not only because that dose ensures sufficient concentration of the ultimate toxicant at the target site to initiate injury, but also because that __ | .
1 efficiency of repair
2 Quantity of toxicant causes DEGREE OF DAMAGE sufficient to compromise repair, allowing progression of the injury. |
| F. TOXICITY RESULTING FROM DYSREPAIR
1) Tissue Necrosis
1 Tissue necrosis occurs because the
INJURY OVERWHELMS AND DISABLES
THE REPAIR MECHANISMS, INCLUDING: | (1) Repair of damaged molecules,
(2) Elimination of damaged cells by
apoptosis,
(3) Replacement of lost cells by cell division. |
| F. TOXICITY RESULTING FROM DYSREPAIR
2) Fibrosis
1 a PATHOLOGIC CONDITION characterized by EXCESSIVE DEPOSITION OF AN EXTRACELLULAR
MATRIX of abnormal composition, is a specific manifestation of dysrepair of the injured tissue.
- IF INCREASED PRODUCTION OF EXTRACELLULAR MATRIX is NOT HALTED, this develops | .
1 Fibrosis |
| F. TOXICITY RESULTING FROM DYSREPAIR
2) Fibrosis
1 a MAJOR MEDIATOR of FIBROGENESIS.
- increased expression of this is a common response
mediating regeneration of the extracellular matrix after
an acute injury. | .
1 (Transforming growth factor-β) TGFβ |
| F. TOXICITY RESULTING FROM DYSREPAIR
2) Fibrosis
1 TGFβ production ceases when __
2 Failure to halt TGFβ overproduction, which leads
to fibrosis, could be caused by __ | .
1 repair complete
2 Continuous injury or a
Defect in the regulation of TGFβ |
| F. TOXICITY RESULTING FROM DYSREPAIR
2) Fibrosis
1 The fibrotic action of TGFβ is due
to:
2 Basement membrane components, such as __, INCREASE DISPROPORTIONATELY DURING
FIBROGENESIS. | .
1) 1 Stimulation of the synthesis of individual matrix components by specific target cells
2 Inhibition of matrix degradation
2) Collagens and Laminin |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis
involves inappropriate function of various
repair mechanisms, including
(1) failure of DNA repair,
(2) failure of apoptosis, and
(3) failure to terminate cell proliferation | Chemical Carcinogenesis |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 may induce neoplastic transformation of cells by genotoxic and nongenotoxic mechanisms.
2 Chemicals that react with DNA may cause damage such as __ | .
1 Chemical and Physical insults
2 Adduct formation,
Oxidative alteration, and
Strand breakage. |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 If lesions are NOT REPAIRED or injured cells are
NOT ELIMINATED, a LESION IN THE PARENTAL DNA STRAND may induce a __in the daughter strand during replication.
2 are HIGHLY CONSERVED genes encoding proteins that stimulate progression of cells through the cell cycle. | .
1 heritable alteration, or mutation,
2 Protooncogenes |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 The products of protooncogenes
include: | .
(1) growth factors;
(2) growth factor receptors;
(3) intracellular signal transducers
such as G proteins, protein kinases, cyclins, and cyclindependent protein kinases; and
(4) nuclear (transcription factor) TFs |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 Transient increases in the production or activity of
__ are required for regulated growth, as during embryogenesis, tissue regeneration, and stimulation of cells by growth factors or hormones.
2 In contrast, permanent activation and/or overexpression of these favors __ | .
1 Protooncogene proteins
2 Neoplastic transformation. |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 One mechanism whereby genotoxic carcinogens INDUCE NEOPLASTIC CELL TRANSFORMATION is by:
2 The Altered gene, called __, encodes a permanently active protein that forces the cell into the division cycle. | .
1 Producing an ACTIVATING MUTATION
of a PROTOONCOGENE
2 oncogene |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; a) Failure of DNA Repair: Mutation, the Initiating Event in Carcinogenesis
1 Encode proteins that inhibit the progression of cells in the division cycle,which include cyclindependent protein kinase inhibitors, TFs that transactivate genes encoding cyclindependent protein kinase inhibitors, and
proteins that block TFs involved in DNA synthesis and cell | .
1 Tumor suppressor genes |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; b) Failure of Apoptosis: Promotion of Mutation and Clonal Growth
1 have MUCH HIGHER APOPTOTIC ACTIVITY than do normal cells.
2 apoptosis counteracts __ of the initiated cells and tumor cells.
3 Facilitation of apoptosis can induce __ | .
1 Preneoplastic cells, or cells with mutations
2 clonal expansion
3 tumor regression, |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; b) Failure of Apoptosis: Promotion of Mutation and Clonal Growth
1 Inhibition of apoptosis is DANGEROUS
because __ of preneoplastic cells are facilitated. | .
1 Mutations and Clonal expansion |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; c) Failure to terminate Proliferation:
Promotion of Mutation, Proto- Oncogene Expression, and Clonal Growth
1 ENHANCED MITOTIC ACTIVITY PROMOTES
CARCINOGENESIS for a number of reasons: | .
1. Enhanced mitotic activity increases
the probability of mutations
2 Overproduced protooncogene proteins cooperate with oncogene proteins to facilitate the neoplastic
transformation of cells
3 Cell to cell communication are temporarily
disrupted during proliferation; contributes to the invasiveness of tumor cells |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; d) Nongenotoxic Carcinogens:
Promoters of Mitosis and Inhibitors of Apoptosis
1 these chemicals cause cancer by PROMOTING CARCINOGENESIS INITIATED BY GENOTOXIC AGENTS or spontaneous DNA damage.
2) occurs in normal human cells at a rate of 1 out of
108 to 1010 base pairs
3 Increase the frequency of spontaneous mutations through a mitogenic effect and by inhibiting apoptosis, thereby increasing the number of cells with DNA damage and mutations. | .
1 Designated nongenotoxic or Epigenetic carcinogens
2 Spontaneous DNA damage
3 Nongenotoxic carcinogens |
| F. TOXICITY RESULTING FROM DYSREPAIR
3) Carcinogenesis ; d) Nongenotoxic Carcinogens:
Promoters of Mitosis and Inhibitors of Apoptosis
1 Cell injury evokes release of MITOGENIC GROWTH FACTORS like __ from tissue macrophages and endothelial cells.
2 So, cells in chronically injured tissues are exposed continuously to __
3 Growth factors continuous presence is potentially harmful because they transform affected cells to __ | .
1) (Hepatocyte Growth Factor) HGF and (Transforming Growth Factor Alpha) TGFα
2 Endogenous mitogens.
3 neoplastic cells |
