Lecture 4- Basic mechanisms of Toxicants 2

what are chemicals that inhibit cellular respiration doing

inhibitors of proteins

or enzymes involved in oxygen consumption, fuel utilization, and ATP

production - cause energy depletion and cell death

example of chemicals that inhibit cellular respiration

cyanide inhibits cytochrome c oxidase to prevent cellular respiration

what does carbon monoxide do

displaces oxygen from hemoglobin causing hypoxia

examples of chemicals that inhibit the production of cellular building blocks

nucleotides, lipids, AA

what organs are particularly susceptible to toxin damage

liver and kidney

hepatic necrossi

acetaminophen poisoning

hepatic inflammation (hepatitis)

halothane can covalently bind to liver proteins to trigger an autoimmune reaction

(one reason it’s rarely used any longer in general anesthesia)

chronic liver damage (cirrhosis)

long term sub clinical toxicant causes cellular toxicity and inflammation

changes in glomerular fliration rate (GFR)

Largely due to drugs that alter blood flow :

NSAIDs (eg. aspirin) reduce prostaglandins which in turn reduces blood flow/GFR

ACE inhibitors (eg. ramipril) increase blood flow/GFR

allergic nephritis

allergic reaction to NSAIDs and antibiotics

chronic nephritis

long term NSAID and acetominophen use

chemicals that caue DNA adducts can lead to

DNA mutations which can activate cell death

pathways; if mutations activate oncogenes or inactivate tumor suppressors, it can lead to

uncontrolled cell proliferation and cancer (e.g. benzo[a]pyrene)

chemicals that cause oxidative stress

can oxidize DNA or proteins leading to DNA mutations or

protein dysfunction and all of the above. (e.g. benzene, CCl4)

chemicals causing the following:

• DNA adducts

• protein adducts

• oxidative stress

can also cause

inflammation which can lead to further cellular dysfunction

apoptosis

necrosis

mechanisms of necrosis

three primary metabolic disorders jepardizing cell survival

ATP depletion

direct conseuqences of ATP depletion

inhibitors of electron transport

inhibitors of oxygen delivery

1. Ischemic agents such as ergot alkaloids, cocaine

2. Carbon monoxide—displaces oxygen from hemoglobin

inhibtors of ADP phosphorylation

DDTm DIM, phytochemicals

chemicals causing mitochondrial DNA damage

antivirals

Ca is involved in (6)

1. signal transduction regulation (i.e. PKC activation by DAG and Ca2+) and exocytosis

2. muscle contraction (actin/myosin interaction)

3. cytoskeletal polymerization (i.e. Ca2+ inhibition of actin)

4. neurotransmission (via glutamate receptor Ca2+ channel and voltage-gated Ca2+

channels) and synaptic plasticity

5. enzyme induction (i.e. citrate and α-ketoglutarate dehydrogenases from the TCA cycle)

6. Transporters (Ca2+/ATPase, Na/Ca2+ exchanger, etc.)

intracellular Ca levels are ________ under normal conditions

highly regulated

The 10,000-fold difference between extracellular and cytosolic Ca2+ concentration is

maintained by:

impermeability of plasma membrane to Ca2+

transport mechanisms that remove Ca2+ from cytoplasm

Ca sources are from

outside cell or Ca2+ stores in ER or mitochondria (as calcium

phosphate).

four mechanisms of calcium elimination

1. Extracellular Ca2+ ATPase

2. Endoplasmic reticulum Ca2+ ATPase

3. Extracellular Na+/ Ca2+ exchanger

4. Mitochondrial Ca2+ uniporter

excitoxicirty

consequence of increased intracellular Ca

what are the 4 parts of exictotoxicity

1. Depletion of energy reserves—decreased mitochondrial ATP production and

increased loss of ATP

2. Dysfunction of microfilaments—impaired cell motility, disruption in cell

morphology, impairment of cellular functions

3. Activation of hydrolytic enzymes—disintegration of membranes, proteins, DNA, etc.

4. Generation of ROS/RNS—disintegration of membranes, proteins, DNA, etc.