| 1 When a toxicant is delivered intended target, it reacts with it and causes 1 __ which leads to 2 __
2 Sometimes, the toxicant will not reach its target
molecule but rather it can adversely influence the
__, causing __ | 1) 1 cellular dysfunction
2 toxicity
2)
1 biological environment
2 molecular, organellar, cellular, or organ
dysfunction leading to deleterious effects.
So its much worse if a toxicant does not reach the target site |
| Mechanism of Toxicity STEPS | Step 1 - Delivery
- Delivery of toxicant to its target molecule.
Step 2 - Either INTERACT w/ MOLECULES or
ALTER ENVIRONMENT
Step 3 - Trigger perturbation in cell function/structure
- changing the normal state of cell function in other
molecules.
Step 4 - Initiate repair
- Body initiate repair mechanisms at cellular/ tissue level
- If beyond repair, toxicity occurs
DIAI (DIAY) |
| the CHEMICAL SPECIES that REACTS WITH
THE ENDOGENOUS TARGET MOLECULE
or CRITICALLY ALTERS THE BIOLOGICAL
ENVIRONMENT, initiating structural and/or functional ALTERATIONS that result in toxicity.
It CAN BE:
- can be the ORIGINAL CHEMICAL to which the
organism is exposed to (Parent Compound)
- can be the a metabolite or a REACTIVE OXYGEN OR NITROGEN SPECIES (ROS or RNS) during the BIOTRANSFORMATION of the toxicant
- can be ENDOGENOUS MOLECULE | Ultimate Toxicant |
| (STEP 1 --- DELIVERY: FROM THE SITE OF
EXPOSURE TO THE TARGET)
1 Theoretically, the ultimate toxicant's concentration and persistence at the site of action determine __
2 The CONCENTRATION of the ULTIMATE TOXICANT at the target molecule depends on the __ | .
1 how STRONG/INTENSE a toxic effect will be.
2 relative effectiveness of the PROCESSES that INCREASE or DECREASE ITS CONCENTRATION at the target site |
| (STEP 1 --- DELIVERY: FROM THE SITE OF
EXPOSURE TO THE TARGET)
ULTIMATE TOXICANT
1 Its INCREASED CONCENTRATION is
facilitated by __
2 DECREASED CONCENTRATION is
facilitated by __ | .
1 - Absorption,
- Distribution to the site of action,
- Reabsorption, and
- Toxication
ADR T
2 - Presystemic elimination,
- Distribution away from the site of action,
- Excretion, and
- Detoxication.
PDED |
| A. ABSORPTION VS PRESYSTEMIC
ELIMINATION
1 is the process by which a CHEMICAL IS TRANSFERRED FROM THE SITE OF EXPOSURE, usually an internal or external body surface, INTO the SYSTEMIC CIRCULATION.
2 Factors that influence this: | 1 Absorption
2 Concentration
Surface area of exposure
Characteristics of the epithelial layer through which
the toxicant is being absorbed
lipid solubility (MOST IMPORTANT) |
| A. ABSORPTION VS PRESYSTEMIC
ELIMINATION
1 Toxicants may be eliminated as they move from the site of exposure to the systemic circulation.
COMMON for CHEMICALS ABSORBED FROM THE GASTROINTESTINAL (GI) TRACT - they must first pass through the GI mucosal cells, liver, and lung before being distributed to the rest of the body by the systemic circulation.
generally REDUCES THE TOXIC EFFECTS OF CHEMICALS that reach their target sites by way of
the systemic circulation.
- may CONTRIBUTE TO INJURY to these sites (digestive mucosa, liver, & lungs)
2 The __may eliminate a significant fraction of a toxicant during its passage through these tissues | 1 PRESYSTEMIC ELIMINATION
2 GI mucosa and the liver |
| B. DISTRIBUTION TO AND AWAY FROM
THE TARGET
1 Toxicants exit the blood during the __, travel through the extracellular space, and reach their target site, which is a __on the exterior or interior of a specific type of cell.
2 Chemicals also may be distributed to the site or sites of toxication, which is an __, where the ultimate toxicant is formed through __ | .
1 distribution phase,
macromolecule
2 intracellular enzyme,
biotransformation |
| B. DISTRIBUTION TO AND AWAY FROM
THE TARGET
1 Mechanisms facilitating DISTRIBUTION TO A TARGET | 1) Porosity of the Capillary Endothelium
2) Specialized Transport Across the Membrane
3) Accumulation in Cell Organelles
4) Reversible Intracellular Binding
PaSAR (naka PaSAR) |
| (Mechanisms facilitating DISTRIBUTION TO A TARGET)
- Porosity of the Capillary Endothelium
Endothelial cells in the hepatic sinusoids and in the renal peritubular capillaries have __ which has a diameter of __ that permit passage of even __ | 1 large fenestrae (opening)
2 (50 to 150 nm in diameter)
3 protein bound xenobiotics |
| (Mechanisms facilitating DISTRIBUTION TO A TARGET)
- Specialized Transport Across the Membrane
1 __ can contribute to the delivery of toxicants to intracellular targets.
2 __ FACILITATE the ENTRY of TOXICANTS into specific cells, rendering those cells targets.
3 The __ of some TOXICANT– PROTEIN COMPLEXES occurs in some
cells as well. | .
1 Specialized ion channels and Membrane transporters
2)
1 Na+ & K+ ATPase,
2 Voltagegated Ca2+ channels,
3 Carrier-mediated uptake,
4 Endocytosis, and
5 Membrane recycling
3) Endocytosis |
| (Mechanisms facilitating DISTRIBUTION TO A TARGET)
- Accumulation in Cell Organelles
1 __ accumulate in lysosomes as well as mitochondria.
2 Lysosomal accumulation OCCURS BY __, that is, DIFFUSION OF THE AMINE in UNPROTONATED FORM into the ACIDIC INTERIOR of the organelle, where the amine is protonated, PREVENTING its EFFLUX, so that it IMPAIRS PHOSPHOLIPID DEGRADATION.
3 Mitochondrial accumulation takes place __.
The AMINE is PROTONATED in the INTERMEMBRANE SPACE and then sucked into the matrix space by the STRONG NEGATIVE POTENTIAL
(–220 mV), where it may IMPAIR β OXIDATION and OXIDATIVE PHOSPHORYLATION. | .
1 Amphipathic xenobiotics w/ protonatable amine group and
lipophilic character
2 pH TRAPPING
3 Electrophoretically. |
| (Mechanisms facilitating DISTRIBUTION TO A TARGET)
- Reversible Intracellular Binding
1 Chemicals that BIND to MELANIN, such as __ accumulate in cells
that contain melanin | .
1 organic and inorganic cations
2 polycyclic aromatic hydrocarbons |
| B. DISTRIBUTION TO AND AWAY FROM
THE TARGET
1 Mechanisms OPPOSING DISTRIBUTION TO A TARGET | 1) Binding to Plasma Proteins
2 Specialized Barriers
3 Distribution to Storage Sites
4 Association with Intracellular Binding Proteins
5 Export from Cells |
| (Mechanisms OPPOSING DISTRIBUTION TO A TARGET)
- Binding to Plasma Proteins
Most xenobiotics must __ from proteins in order to leave the
blood and enter cells. As a result, the EFFECTS & ELIMINATION of
TOXICANTS are DELAYED & PROLONGED by __ to plasma proteins. | .
1 dissociate
2 strong binding |
| (Mechanisms OPPOSING DISTRIBUTION TO A TARGET)
- Specialized Barriers
1 Because brain capillaries LACK __ and have extremely tight
junctions, substances that are __ CANNOT ENTER THE BRAIN except by
__
2 The spermatogenic cells are surrounded by __ that are
tightly joined to form the __.
3 Transfer of HYDROPHILIC TOXICANTS across the placenta is RESTRICTED. However, NONE of these BARRIERS are EFFECTIVE AGAINST __ | .
1) 1 fenestrae
2 hydrophilic,
3 active transport
2) 1 Sertoli cells,
2 blood–testis barrier
3 lipophilic substances.
Hydrophilic = Restricted
Lipophilic = Not Restricted |
| (Mechanisms OPPOSING DISTRIBUTION TO A TARGET)
- Distribution to Storage Sites
1 Some chemicals accumulate in tissues (i.e., storage sites) where
they exert __
2 Such storage __ toxicant availability for their target site | .
1 NO significant effects.
2 decreases |
| (Mechanisms OPPOSING DISTRIBUTION TO A TARGET)
- Association with Intracellular Binding Proteins
1 Binding to NONTARGET INTRACELLULAR SITES, such as __, TEMPORARILY REDUCES the CONCENTRATION OF TOXICANTS at the target site. | .
1 metallothionein |
| (Mechanisms OPPOSING DISTRIBUTION TO A TARGET)
- Export from Cells
1 Intracellular toxicants may be transported back into the __
2 The ATP-dependent MEMBRANE TRANSPORTER FAMILY that is known as the __ EXTRUDES CHEMICALS FROM CELLS | .
1 extracellular space
2 multi-drug resistant proteins or MDR proteins |
