1212569_21823227.jpg logo_mu_cerne.gif 1212570_28446780.jpg logo_mu_cerne.gif
 Luděk Bláha, PřF MU, RECETOX
www.recetox.cz
BIOMARKERS AND TOXICITY MECHANISMS
02 – MECHANISMS OVERVIEW
OPVK_MU_stred_2

1212569_21823227.jpg logo_mu_cerne.gif
Different categorizations of MoA
•According to target molecules (next slide)
–Mechanisms primarily targeting different
•BIOLOGICAL MACROMOLECULES
–i.e. PROTEINS and/or NUCLEIC ACIDS and/or PHOSPHOLIPIDS
•SMALL BIOLOGICAL (ORGANIC) MOLECULES
–E.g. Antioxidants or scavengers (vit.E, GSH)
•
•According to INTERACTION between toxicant/target (next slide)
–Non-covalent interactions
•Partitioning (v d Waals, H-bonds, hydrophobic interactions) à [1] below
•Partitioning with specific steric fit à [3] below
–Formation of covalent bonds
•... with proteins / DNA-RNA / P-lipids / small molecules   à [2] below
•
•According to “STERIC SPECIFICITY” of the interaction
–NON-SPECIFIC MECHANISMS
•the  interaction between the toxicant and the target occurs “generally” with any target of certain
general properties (e.g. toxicant is able to bind to ANY protein having e.g. SH- group), it does
not require specific steric (structural) properties of the target
–mechanisms [1] and [2] below
–SPECIFIC MECHANISMS
•the toxicant interacts only with certain and specific structural properties (e.g. specific binding
of a pesticide into the active site of enzyme acetylcholinesterase)
–mechanism [3]
•

1212569_21823227.jpg logo_mu_cerne.gif
Target (receptor) in MoA / toxicodynamic = BIOMOLECULE
[1]
[3]
[2]

1212569_21823227.jpg logo_mu_cerne.gif
Possible categorizations of MoA
•[1] non/specific membrane toxicity
–Involves ALL ORGANIC compounds
–Affinity to non-polar environment (membrane phospholipids)
–Two types can be discriminated
•nonpolar basal / narcotic toxicity (
–effects observed at relatively high concentrations, depends on hydrophobicity (Kow)
•polar narcosis
–more polar compounds may affect also membrane proteins (effects at lower concentrations than
expected from Kow)
•
•[2] nonspecific reactive toxicity
–some compounds with “reactive” properties may directly modify biological macromolecule (lipids,
proteins, nucleic acids) causing thus toxic effects
–reactive chemicals are mostly „electrophiles“ (reacting with „nucleophiles“ in cells – i.e.
electrone-rich sites - nucleotides, -NH2, -SH and others)
•
•[3] specific steric interactions
–only certain specific compounds selectively affect specific targets
–E.g. enzyme inhibitions (drugs, insecticides); receptor interactions (e.g. Estrogens)
–Can be non-covalent as well as covalent
–Effects at very low concentrations
All organics
à membranes
Reactive

1212569_21823227.jpg logo_mu_cerne.gif
Possible categorizations of MoA
•Species-specific mechanisms, examples
–photosynthetic toxicity (only in plants) vs. teratogenicity (only in vertebrates)
–Endocrine disruption
•different hormonal systems in invertebrates vs vertebrates
à different toxicity mechanisms
Growth in invertebrates
ecdysis (moulting) - ecdysteroids
http://img.docstoccdn.com/thumb/orig/8860991.png
Growth in humans
several hormones

1212569_21823227.jpg logo_mu_cerne.gif
Possible categorizations of MoA
•- Tissue-specific mechanisms (& effects)
• - hepatotoxicity; neurotoxicity; nefrotoxicity; haematotoxicity
• - toxicity to reproduction organs;
• - immunotoxicity
•
•
•
•
•
•
•
•
•
•Developmental stage-specific mechanisms
-- embryotoxicity/teratogenicity: toxicity to cell differenciation processes
http://img2.allvoices.com/thumbs/image/609/480/103574038-diclofenac-drug.jpg
http://www.painstopanswers.com/images/diclofenac.jpg
Thalidomide
Cyanobacterial metabolites
Fig2C Fig2B
Malformations in frog tadpoles

1212569_21823227.jpg logo_mu_cerne.gif
Keywords to remember and understand
•What is it MoA?
•Can you give examples of species-specific MoA?
•What are the biological targets for toxicants? How can they be classified? •What are the possible
interactions between toxicants and biological targets?
•What is it specific and non-specific toxicity mechanism?
•What biological molecules are likely to be affected (usually at relatively high concentrations) by
ALL ORGANIC COMPOUNDS?
•
•
• .... and now let’s look in detail on major MoAs
and their toxic consequences

1212569_21823227.jpg logo_mu_cerne.gif
•Student is expected to know principles and some examples of the following main types of toxicity
mechanisms
•Proteins and inhibition of enzymatic activities
•Mitotic poisons & microtubule toxicity
•Ligand competitions – receptor mediated toxicity
•
•Membrane nonspecific toxicity (narcosis)
•Toxicity to membrane gradients (also includes proteins)
•
•DNA toxicity (genotoxicity)
•
•Complex mechanisms
–Oxidative stress – redox toxicity
–Defence processes as toxicity mechanisms and biomarkers - detoxification and stress protein
induction
–Toxicity to signal transduction
–
Toxicity mechanisms - overview