Mechanisms of Toxicity IV

Question 1

Oxidative Phosphorylation (ATP synthesis)

Answer 1

How we obtain energy
- glucose > pyruvate > PDH> Acetyl-CoA > creb cycle > NADH+H+> H+ & e- > electron transport chain
- Fatty acids > Fatty acyl-CoA> beta OX> Acetyl-CoA> creb cycle > NADH+H+> H+ & e- > electron transport chain

= O2> 2H2O
= Pi
=ADP
= ATP

Question 2

Impaired ATP synthesis
xenobiotic Target A

Answer 2

Delivery of hydrogen to electron transport chain (ETC) in the form of NADH
- e.g. arsenite inhibits pyruvate dehydrogenase (PDH complex converting pyruvate to acetyl-CoA)
-e.g. fluoroacetate (rodenticide) inhibits enzyme aconitase in citric acid cycle

Question 3

Xenobiotic target B

Answer 3

Impaired function of ETC
- e.g. rotenone (pesticide) inhibits NADH-coenzyme Q reductase (Complex I)
- e.g. cyanide inhibits cytochrome c oxidase (Complex IV)

Question 4

xenobiotic target C

Answer 4

Impaired delivery of O2 as terminal electron acceptor
- e.g. carbon monoxide (CO) displaces O2 on hemoglobin

Question 5

xenobiotic target D

Answer 5

Inhibition of ADP phosphorylation
- e.g. chlordecone (insecticide) inhibits ATP synthase
- e.g. xenobiotics that “uncouple” (disrupt) the electrochemical (proton) gradient across inner mitochondrial membrane, which is the driving force for ATP synthase:
- Pentachlorophenol (fungicide) is an ionophore that causes protons to “leak” back into inner mitochondrial matrix
-Dinitrophenols (herbicides) donate protons to the inner mitochondrial matrix

Question 6

Sustained rise of intracellular Ca++ - Mechanisms of toxic cell death

Answer 6

• Ca++ ion is maintained at a 10,000x greater concentration extracellularly than intracellularly; disruption of Ca++ homeostasis is a major mechanism of toxic cell death

Question 7

Sustained rise of intracellular Ca++ - Mechanisms of toxic cell death - continued

Answer 7

• Ca++ homeostasis is maintained by active transport from the cytoplasm to extracellular space and by sequestration from cytoplasm into mitochondria and endoplasmic reticulum (ER)

Question 8

xenobiotics in the mechanisms of toxic cell death act to:

Answer 8

-promote influx or inhibit efflux from cytoplasm
-cause leakage from mitochondria and ER into cytoplasm

Question 9

Other mechanisms of cell death

Answer 9

-disrupt protein synthesis
-e.g ethanol
- Destroy cytoskeleton, specifically microtubules involved in mitosis and other cellular functions
- e.g. colchicine (chemotherapy drug)
- Direct damage to plasma membrane
- e.g. nonpolar solvents, detergents, and reactive oxygen species (ROS)
apoptosis/necrosis

Question 10

Impaired external maintenance

Answer 10

“impaired function of integrated systems”
-inhibition of hepatic synthesis of coagulation factors
- e.g. warfarin (rodenticide and “blood thinner” drug) inhibits activation of vitamin K needed for production of clotting factors
used for heart attacks or strokes