Oxidative Stres pt. 3 Flashcards Preview

Toxicology > Oxidative Stres pt. 3 > Flashcards

Flashcards in Oxidative Stres pt. 3 Deck (16)
Loading flashcards...
1
Q

paraquat

A

a highly effective, fast-acting and nonselective herbicide

highly toxic to human beings and animals

2
Q

what happens when paraquat enters the cell?

A

it undergoes redox cycling reaction and generates a superoxide anion radical

3
Q

chronic exposure to paraquat is associated with

A

liver damage, kidney failure and Parkinsonian lesions

4
Q

anthracycline antibiotic doxorubicin (DOX) is one of the most effective

A

anticancer drugs for treating various types of cancers such as carcinomas

5
Q

DOX can generate ROX via 2 distinct mechanisms: 1. forming a complex with cardiolipin ETC

A

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

6
Q

DOX can generate ROX via 2 distinct mechanisms: 2. DOX binds avidly to iron

A

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

7
Q

MPTP is

A

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+

8
Q

MPP+ is believed to

A

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

9
Q

disruption of complex I in the ETC due to MPP+ causes a decrease in

A

generation of ATP and a resulting increase in intracellular calcium levels

10
Q

chronic consumption of alcohol can lead to

A

hepatocyte cell death, cirrhosis and cancer

11
Q

individual consumes moderate amounts of ethanol

A

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

12
Q

mutation in aldehyde dehyrogenase 2 causes what?

A

diminishes the enzyme activity and causes “asian flush”

13
Q

ROS + Alcohol Toxicity - the increased NADH/NAD ratio due to metabolism of alcohol will cause 4 possible things

A
  1. increase the production of superoxide in liver mitochondria due to the increased flux of NADH into the ETC
  2. inhibit citric acid cycle by inhibiting the enzymes isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase which causes a decrease in the generation of ATP
  3. inhibit gluconeogenesis by promoting the enzyme lactate dehydrogenase (LDH) which leads to lactic acidosis and hypoglycemia
  4. 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)
14
Q

chronic ethanol exposure induces the expression of

A

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

15
Q

CYP2E1 contributes to the alcohol-induced liver injury in rodents

A
  1. CYP2E1 inhibitors attenuate alcohol-induced liver injury in rats
  2. transgenic mice over-expressing CYP2E1 display a higher degree of liver injury in response to ethanol treatment than wild-type mice
  3. KO mice are markedly more resistant to alcohol-induced hepatic steatosis (fatty liver) AND oxidative stress (lipid peroxidation) than the wild type mice were
16
Q

genotoxicity of acetaldehyde

A
  1. chronic consumption of alcohol is thought to contribute to approximately 3.6% of all cancers worldwide (due to the generation of acetaldehyde)
  2. KO mice lacking both ALDH2 and FANCD2 (which is a downstream protein, are significantly susceptible to ethanol exposure and develop acute T-cell leukemia at 3-6mon. of age