Lecture 2 - fatty acid oxidation inhibition Flashcards
What are the types of mitochondrial toxicity?
Inhibition of electron transport chain, uncoupling of oxidative phosphorylation, inhibition of mtDNA synthesis, opening of permeability transition pore and inhibiton of fatty acid oxidation
How does inhibition of mitochondrial beta-oxidation occur?
Mostly achieved by structural analogues of fatty acids that compete at one of the enzymatic steps. This results in decrease in ATP production and accumulation of long-chain acyl-CoAs, FAs and triglycerides
What are examples of inhibitors of B-oxidation?
Amiodarone, Benzbromaron, Buprenorphine, Tolcapone, Valproate
How can you determine/measure B-oxidation and fat accumulation?
Measurement of palmitate, C-acetyl-CoA and Ketone bodies (hepatocytes) or CO2 (muscle cells).
determine triglycerides in cells and tissues using staining or saponification
determine carnitine derivatives in plasma and urine using LC-MS
What are important enzymes involved in mitochondrial FA metabolism?
Acyl-CoA synthase, CPT1 (carnitine to acylcarnitine), translocase and CPT II
Why were CPT II inhibitors developed and what do they do?
treatments for DT2 and they inhibit gluconeogensis and reduce glucose production
What is fatty liver of pregnancy?
Disease occurring in final stages of pregnancy and occurs because FA metabolism intermediates are exported from child to mother which results in impairment of hepatic mitochondrial function of the mother
What are the diffential diagnosis of microvesicular steatosis?
Metabolism diseases (fatty livers of pregnancy), Reye’s syndrome, Toxic liver injuries (occuring by drugs - valproate, amiodarone, tetracycline and toxicants/toxins)
How does tolcapone affect hepatic FA metabolism?
decreased the activity of long-acyl-CoA dehydrogenase
how does COMT inhibitors effect triglyceride export?
reduction of ApoB100 mRNA expression
How does valproate affect liver toxicity?
Depletion of CoASH and carnitine. Has toxic metabolites that inhibit beta-oxidation and respiratory chain