Detoxification and Molecular Therapy
23 important questions on Detoxification and Molecular Therapy
What are the detoxification phases?
2. Oxidation (CYP enzymes) & Conjugation (sulfotransferases, UDP glucuronsyltransferase).
3. Excretion (urine, bile)
* With every step more soluble
Where does drug biotransformation take place?
What is enterohepatic circulation?
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How does the metabolism of Acetaminophen (Paracetamol) go? And in case of overdose?
However, when these pathways are overloaded by too much acetaminophen the drug will be oxidized by CYP450 making NAPQI, which is toxic. NAPQI react with glutathione to lose the toxicity, however the depletion of glutathione is even more toxic because it acts as a defense against oxidative stress.
Why is acetaminophen (paracetamol) less toxic together with alcohol use? And why more toxic in case of chronic alcohol use?
How does bile get transported?
ABC transporters transport the bile.
How does the drug uptake go? And the excretion?
The ABC transporters pump the drug from the liver into the intestine.
ABC transports transport drugs, toxins and waste products.
How does the Pregnane X receptor regulate drug metabolism?
The PXR ligand bind to PXR, casusing dimerization and its translocation into the nucleus. There it binds to promotor, increasing the transcription of CYP.
CYP3A!!
Why St. Johns wort cause ineffective drug function?
How does grapefruit affect drug metabolism?
What does UDP glucuronyltransferase do?
Substrate + UDPGA --> Substrate-glucuronide + UDP
Which drug becomes more active after glucuronidation?
What is the importance of UGT in the detoxification of endogenous compounds?
- Inactivation of steroid hormones.
- Inactivation f the heme metabolite bilirubin.
What is recycles and what excreted in the degradation of heme?
How does the degradation of Hemoglobin go?
What is a byproduct of heme-metabolism?
It can be a regulator of many physiologic processes.
What functions has the heme metabolism other than detoxification?
- Bilirubin is an antioxidant
What happens when someone has liver damage?
However, the conjugated form of bilirubin is less toxic (importance UGT!)
What is the Cringler-Najjar disease?
Deficiency in UGT1A1. Bilurubin cannot be excreted efficiently.
What is the Gilbert syndrome?
The bilirubin UGT promotor has different variations; TATA box with 6 or 7 TA's. The 7 TA has a lower activity.
What is the effect of bilirubin UGT promotor polymorphisms together with glucose 6 phosphate dehydrogenase (G6PD) deficiency?
Children with the 7TA UGT and G6PD deficiency can have life threatening high serum bilirubin at birth.
* G6PD is involved in the PPP
* G6PD deficiency is protective against malaria
How does light therapy help Cringler-Najjar disease?
When bilirubin is exposed to light in unfolds, which leaves the carboxylgroups exposed. This makes the molecule more soluble and therefore easier to be transported/excreted.
What are the treatment options for Cringler-Najjar disease?
- Liver transplantation (curative)
- Gene therapy
- Metabolic approach (inhibit production of bilirubin or facilitate excretion)
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