Author: Timo Hamers
Reviewers: Frank van Belleghem and Ludek Blaha
Learning goals
You should be able to
- explain that a toxic response requires a molecular interaction between a toxic compound and its target
- name at least three different types of biomolecular targets
- name at least three functions of proteins that can be hampered by toxic compounds
- explain in general terms the consequences of molecular interaction with a receptor protein, an enzyme, a transporter protein, a DNA molecule, and a membrane lipid bilayer.
Key words: Receptor; Transcription factor; DNA adducts; Membrane; Oxidative stress
Description
Toxicodynamics describes the dynamic interactions between a compound and its biological target, leading ultimately to an (adverse) effect. In this Chapter 4.2, toxicodynamics have been described for processes leading to diverse adverse effects. Any adverse effects by a toxic substance is the result of an interaction between the toxicant and its biomolecular target (i.e. mechanism of action). Biomolecular targets include a protein, a DNA or RNA molecule, a phospholipid bilayer membrane, but also small molecules that have specific functions in keeping cellular homeostasis.
Both endogenous and xenobiotic compounds that bind to proteins are called ligands. The consequence of a protein interaction depends on the role of the target protein, e.g.
1. Receptor
2. Enzyme
3. Protein
Receptor proteins specifically bind and respond to endogenous signalling ligands such as hormones, prostaglandins, growth factors, or neurotransmitters, by causing a typical cellular response. Receptor proteins can be located in the cell membrane, in the cytosol, and in the nucleus of a cell. Agonistic receptor ligands activate the receptor protein whereas antagonistic ligands inactivate the receptor and prevent (endogenous) agonists from activating the receptor. Based on the role of the receptor protein, binding by ligands may interfere with ion channels, G-protein coupled receptors, enzyme linked receptors, or nuclear receptors. Xenobiotic ligands can interfere with these cellular responses by acting as agonistic or antagonistic ligands (link to section on Receptor interaction).
Compounds that bind to an enzyme usually cause inhibition of the enzyme activity, i.e. a decrease in the conversion rate of the endogenous substrate(s) of the enzyme into its/their corresponding product(s). Compounds that bind non-covalently to an enzyme cause reversible inhibition, while compounds that bind covalently to an enzyme cause irreversible inhibition (link to section on Protein inactivation).
Similarly, compounds that bind to a transporter protein usually inhibit the transport of the natural, endogenous ligand. Such transporter proteins may be responsible for local transport of endogenous ligands across the cell membrane, but also for peripheral transport of endogenous ligands through the blood from one organ to the other (link to section Endocrine disruption).
Apart from interaction with functional receptor, enzyme, or transporter proteins, toxic compounds may also interact with structural proteins. For instance the cytoskeleton may be damaged by toxic compounds that block the polymerization of actin, thereby preventing the formation of filaments.
In addition to proteins, DNA and RNA macromolecules can be targets for compound binding. Especially the guanine base can be covalently bound by electrophilic compounds, such as reactive metabolites. Such DNA adducts may cause copy errors during DNA replication leading to point mutations (link to section on Genotoxicity).
Compounds may also interfere with phospholipid bilayer membranes, especially with the outer cell membrane and with mitochondrial membranes. Compounds disturb the membrane integrity and functioning by partitioning into the lipid bilayer. Lost membrane integrity may ultimately lead to leakage of electrolytes and loss of membrane potential.
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Narcosis and Membrane Damage
Partitioning into the lipid bilayer is a non-specific process. Therefore, concentrations in biological membranes that cause effects through this mode of action do not differ between compounds. As such, this type of toxicity is considered as a “baseline toxicity” (also called “narcosis”), which is exerted by all chemicals. For instance, the chemical concentration in a target membrane causing 50% mortality in a test population is around 50 mmol/kg lipid, irrespective of the species or compound under consideration. Based on external exposure levels, however, compounds do have different narcotic potencies. After all, to reach similar lipid-based internal concentrations, different exposure concentrations are required, depending on the lipid-water partitioning coefficient, which is an intrinsic property of a compound, and not of the species.
Narcotic action is not the only mechanism by which compounds may damage membrane integrity. Compounds called “ionophores”, for instance, act like ion carriers that transport ions across the membrane, thereby disrupting the electrolyte gradient across the membrane. Ionophores should not be confused with compounds that open or close ion channels, although both type of compounds may disrupt the electrolyte gradient across the membrane. The difference is that ionophores dissolve in the bilayer membrane and shuttle transport ions across the membrane themselves, whereas ion channel inhibitors or stimulators close or open, respectively, a protein channel in the membrane that acts as a gate for ion transport.
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Finally, it should be mentioned here that some compounds may cause oxidative stress by increasing the formation of reactive oxygen species (ROS), such as H2O2, O3, O2•-, •OH, NO•, or RO•. ROS are oxygen metabolites that are found in any aerobic living organism. Compounds may directly cause an increase in ROS formation by undergoing redox cycling or interfering with the electron transport chain. Alternatively, compounds may cause an indirect increase in ROS formation by interference with ROS-scavenging antioxidants, ranging from small molecules (e.g. glutathione) to proteins (e.g. catalase or superoxide dismutase). For compounds causing both direct or indirect oxidative stress, it is not the compound itself that has a molecular interaction with the target, but the ROS which may bind covalently to DNA, proteins, and lipids (link to section on Oxidative Stress).
