4: Basic Mechanisms of Toxicants 2

describe chemicals that inhibit cellular respiration?

inhibitors of proteins/enzymes used in O2 consumption, fuel, ATP production

what occurs when chemicals inhibit cellular respiration?

energy depletes and cells die

what does cyanide inhibit?

cytochrome c oxidase

what does carbon monoxide do?

displaces O2 from hemoglobin, causing hypoxia

what chemical inhibits production of cellular building blocks?

amantin (deathcap mushrooms)

cellular building blocks

nucleotides, lipids, AAs, proteins

2 organs most susceptible to toxin damage

liver and kidneys

why are the liver and kidneys most susceptible to toxins?

involved in elimination/processing/exposure, receives lots of CO

3 stages of hepatotoxicity

hepatic necrosis, hepatitis (inflammation), cirrhosis (chronic damage)

what causes hepatic necrosis

acetaminophen poisoning

3 stages of nephrotoxicity

changes in GFR, allergic/chronic neprhitis

what drugs largely affect GFR?

NSAIDS and ACE inhibitors

what happens in allergic nephritis?

allergy to NSAIDS/antibiotics

how does chronic nephritis occur?

long term NSAID use

what can a chemical cause an ADDUCT on?

DNA, proteins

chemicals causing DNA adducts do what?

mutate DNA, form cell proliferations/cancer

chemicals causing protein adducts do what?

cause protein dysfunction, activating cell death pathways/autoimmunity. can also form cell proliferations/cancer

chemicals causing oxidative stress do what?

oxidize DNA/proteins leading to mutations

what can inflammation further lead to?

further cell dysfunction

apoptosis

programmed cell death

what is apoptosis dependent on?

caspases

necrosis

unprogrammed cell death

is necrosis active or passive cell death?

passive

cells must do these:

make endogenous molecules, assemble macro complexes/membranes/organelles, maintain ITC environment, produce energy

what are the main disruptions a toxin can cause on a cell?

protein synthesis and mitochondrial damage

3 primary causes of necrosis

ATP depletion, sustained IC CA, overproduction of ROS/RNS

ATP plays role in what?

cellular maintenance (chemical for biosynthesis and energy source)

when ATP is depleted, what pumps are compromised?

Na/K ATPase and Ca/ATPase

4 agents that impair ATP synthesis

inhibitors of electron transport, O2 delivery, ADP phosphorylation, and chemicals causing mitochondrial DNA damage (antivirals)

true or false: under normal conditions, intracellular Ca levels are HIGHLY REGULATED

TRUE

4 mechanisms of calcium elimination are

ETC Ca ATPase, ER Ca ATPase, ETC NA/CA exchanger, mitochondrial Ca uniporter

excitotoxicity

consequence of increased intracellular Ca

what happens during excitotoxicity?

depletion of energy reserves, microfilament dysfunction, activation of hydrolytic enzymes, ROS/RNS generation

MAIN POINTS ON ATP DEPLETION

causes cell osmolarity disruption and swelling

MAIN POINTS ON INTRACELLULAR CA INCREASE

microfilaments dissociate, membrane blebbing, cell destruction

MAIN POINTS ON ROS/RNS INCREASE

causes lipid peroxidation, membrane destruction, cell swelling and lysis