Oxidative Stres pt. 3 Flashcards
paraquat
a highly effective, fast-acting and nonselective herbicide
highly toxic to human beings and animals
what happens when paraquat enters the cell?
it undergoes redox cycling reaction and generates a superoxide anion radical
chronic exposure to paraquat is associated with
liver damage, kidney failure and Parkinsonian lesions
anthracycline antibiotic doxorubicin (DOX) is one of the most effective
anticancer drugs for treating various types of cancers such as carcinomas
DOX can generate ROX via 2 distinct mechanisms: 1. forming a complex with cardiolipin ETC
the quinone structure of DOX permits it to accept one electron from NADH dehydrogenase of complex I to form a semiquinone radical, this is then oxidized back to the parental compound by passing the electron received onto molecular oxygen to form a molecule of superoxide
DOX can generate ROX via 2 distinct mechanisms: 2. DOX binds avidly to iron
the complex can be reduced to the doxorubicin-iron (II) complex in the presence of reducing agents such as NADPH CYP450 reductase, glutathione and cysteine
this complex can then participate in the Fenton reaction to generate the highly reactive hydroxyl radical
MPTP is
lipophilic and is able to cross the BBB, once inside the brain it’s oxidized by the enzyme monoamine oxidase B which is then auto-oxidized to the toxic cation MPP+
MPP+ is believed to
selectively enter the dopaminergic neurons of the substantia nigra through high affinity dopamine transporters, it then disrupts oxidative phosphorylation by inhibiting complex I of the ETC
disruption of complex I in the ETC due to MPP+ causes a decrease in
generation of ATP and a resulting increase in intracellular calcium levels
chronic consumption of alcohol can lead to
hepatocyte cell death, cirrhosis and cancer
individual consumes moderate amounts of ethanol
most is metabolized by the enzyme alcohol dehydrogenase in the liver - this metabolism results in the generation of the reactive metabolite acetaldehyde and NADH
acetaldehyde is further oxidized by hepatic aldehyde dehydrogenase to acetate which results in the production of NADH
mutation in aldehyde dehyrogenase 2 causes what?
diminishes the enzyme activity and causes “asian flush”
ROS + Alcohol Toxicity - the increased NADH/NAD ratio due to metabolism of alcohol will cause 4 possible things
- increase the production of superoxide in liver mitochondria due to the increased flux of NADH into the ETC
- inhibit citric acid cycle by inhibiting the enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase which causes a decrease in the generation of ATP
- inhibit gluconeogenesis by promoting the enzyme lactate dehydrogenase (LDH) which leads to lactic acidosis and hypoglycemia
- inhibit beta-oxidation of fatty acids by inhibiting the enzyme L-3 hydroxy acyl-CoA dehydrogenase which leads to increased triacylglycerol, increased VLDL production which results in liver steatosis (fatty liver)
chronic ethanol exposure induces the expression of
CYP2E1 protein, largely by a post-transcriptional mechanism involving enzyme stabilization against degradation
-increased levels of CYP2E1 protein may allow it to assume a more important role in the metabolism of alcohol
CYP2E1 contributes to the alcohol-induced liver injury in rodents
- CYP2E1 inhibitors attenuate alcohol-induced liver injury in rats
- transgenic mice over-expressing CYP2E1 display a higher degree of liver injury in response to ethanol treatment than wild-type mice
- KO mice are markedly more resistant to alcohol-induced hepatic steatosis (fatty liver) AND oxidative stress (lipid peroxidation) than the wild type mice were
