Molecular Toxicology Exam 1 Prep (Exam Review Based) Flashcards

Study of the adverse affects of xenobiotics

• formed basics of therapeutics, experimental medicine, environmental health, and fundamental science
• It's important in risk assessment for chemical compounds, medicines, food, etc

• father of modern toxicology (1493-1541)
• Chemical toxic and therapeutic properties are dependent on the dose
• Specifically studied water intoxication

• was a morning sickness medicine
• caused more than 10,000 children to be born with birth defects in Europe and Africa
• Led to discovery of placenta-crossing by Francis Kelsey

Discovered placenta-crossing

• Federal food Drug Cosmetic Act (1938)
• Substances had to be tested for safety of human consumption
• Led to the founding of the FDA (food & drug administration)

• Federal Insecticide, Rodenticide, and Fungicide Act (1947)
• States that a non-food/drug item must be effective and safe

• Antifreeze
• Was added to children's medicine to make it sweet before FDC Act

• TCDD (dioxin)
• Carcinogen used during times of war as a jungle defoliant

• Substances like methanol, lead, and triorthocresyl phosphate being added to alcohol to pass as medicine
• Triorthocresyl phosphate was added to rum to make Jamaican ginger

• Kinetics: concentration of compound in your body
• Very dependent on bioavailability as it has to be able to take up the toxin to have effect as well as uptake and transport
• Dynamics: determines the effect of the toxin
• Dependent on binding type and induction of toxic effects

the phenotypic outcomes of the toxicity of a chemical

• three types: Adaptation, stress response, and toxic response

• physiological response to a "consistent" exposure
• Is possible within a given exposure/time range
• If exposure increases in time or concentration, it becomes toxic

• cellular stress
• Intended to limit the damage to the cell and tissue
• often non-specific
• Variety of conditions: oxidative stress, energy homeostasis, heat stress, and reactive metabolites

• biological phenomenon where a toxic substance in low doses could be beneficial
• The hormetic region is the thin region between the substance being helpful and harmful to the receiving organism

• Main routes: skin, ingestion (GI tract), respiratory
• Lesser routes: injection, maternal transfer (placenta), bite, thorn, abrasion

• mechanism your body has to prevent drug uptake
• cell membrane, epithelial cells of GI tract, respiratory surface aka lung, and body surface

1. How easy it moves across cell membranes

- lipophilicity, movement through ion channels, active or passive transport

2. Characteristics of the epithelium

- mainly epithelial thickness

3. Toxin concentration

- more concentration=faster delivery

4. Structure of capillary beds

- how much vasculature (fenestrated (extremely porous) or no)

5. Does it bind reversibly

1. Plasma proteins: bind to make toxin unavailable
2. Barriers: (ie. BBB) keep toxins out
3. Long term storage: (ie. fat cells) stores toxins to mitigate damage
4. Binding proteins: (ie.metallothionine) to bind and attempt to make toxins useless
5. Metabolism and elimination: break down toxin and excrete out of the body

How hydrophobic or fat soluble is the compound

Their degree of lipophilicity is different

This is a specific example of a compound that partakes in molecular mimicry

• in this specific one, MeHg----Cystine can mimic methionine and cross the BBB to cause neurological issues

Cadmium

• Compound induces production of metallothionine in the liver
• The Cd enters the liver and binds reversibly to the metallothionine
• It runs through your blood stream into your kidney
• Detaches from the metallothionine
• Causes tumor growth in your kidney

1. Diffusion
2. Facilitated Diffusion
3. Active transport
4. Endocytosis

• movement of small lipophilic compounds
• most toxins and compounds pass through this mechanism

• High transport rate thanks to carrier proteins and ion channels (aka mediators)
• highly selective transport option and often temperature dependent
• The transport rate can be inactivated or inhibited (ie.metals)

• Requires ATP-pumps
• Na-K-ATPase
• often important in transport of material out of cells

• actively transport material out of cells
• extremely important from liver and kidneys
• Part of the ABC transporter family

• Form of active transport
• MDR protein
• Encoded by the MDR-1 gene
• Very little specificity; most lipophilic compounds can bind/be moved
• PGP/MDR pumps out chemo drugs from tumor cells which renders the drug ineffective
• Inhibitors are given to keep drug in the tumor cells

• ATP expensive transport/dissolution of large molecule

Drawing: should include macrophage removing stuck molecule in lipid bilayer, dissolution of the molecule, and repair of the bilayer

• Explanation should include more macrophages coming to attempt to digest large molecule and being unsuccessful and emitting reactive oxygen species (ROS)

• differences in cellular transport as it determines how, what form, and where the toxicant enters the cell
• not all cells express specific transporter

MPTP (heroin)

• MPTP is the byproduct of heroin synthesis/metabolization
• leads to parkinsons like symptoms (loss of dopaminergic neurons)
• mimics dopamine enough to use dopamine transporters in brain

• Chemical modifications that introduce a functional group on a xenobiotic that provides sites for phase II metabolism
• "putting a handle on it"
• Takes place in smooth ER of a hepatocyte
• Major enzymes are cytochrome P450 (CYP) or mixed function oxygenase (MFO)

• Synthetic reaction of a xenobiotic with an endogenous substance that results in a product in which is more water soluble and will enhance excretion
• "Something grabs the handle"
• Neutralization of active metabolic intermediates
• Cytoplasm in hepatocyte is the area where reaction takes place
• Important enzymes: GST, EH, UDP-GTS, ST

• GST is in phase II
• takes phase I metabolite and adds glutathionine (protein)

• Phase II
• Detoxifies epoxides

• Phase II
• adds glucuronic acid

• Phase II
• adds sulfer groups

• Cancer drug
• Causes different types of cancer in rats
• ST enzyme example differences in rats and humans

• NSAID pain relievers (like ibuprofen)

• 2-napthylamine
• intermediate formed is more toxic
• Toxicity of the compound is determined by your bladder pH
• Acidic: connection w/acid is unstable which produces protonated compounds in the bladder which leads to bladder cancer
• basic: excreted normally

• change in chemical structure through metabolism
• the parent compound structure is altered

• change in the chemical structure through metabolism that makes the compound MORE reactive/toxic
• not all that are transformed are activated
• Does not occur in all tissues
• has different toxicokinetics and mechanisms
• May be species specific

• 4-ipomeanol
• fungal derived toxin that causes bronchiolar necrosis in most mammals but not humans
• Most mammals produce CYP4B1 enzymes in lungs which means the toxic response is in the lungs
• For humans CYP1A2 and CYP3A4 in liver so the toxic reaction for us is in our liver