Lecture 22: Genetics of GI Disorders Flashcards
What does St. John’s Wort do?
has hyperforin and Hypericin which induces CYP3A4 which chews up steroid meds and a lot of different drugs
What does biotransformation mean?
fat soluble drugs converted to water soluble
What are the phases of drug biotransformation?
Phase 1: Oxidative metabolism (ROHH)
Phase 2: Conjugative metabolism (CSMG)
Phase 3: Drug transport/effux/excretion
How does Rifampicin, Phenobarbital and St. John’s Wort activate the xenobiotic response?
What genes do they upregulate?
they bind to PXR-RXR > upregulate genes that make enzymes for detoxification processes
Phase 1: Cyp3A
Phase 2: UGT1A1
Phase 3: Oatp2, Mrp2
What are the major transporters that absorb the drug in these types of cells?
enterocyte
hepatocyte
kidneys
- OATP
- OATPB1/B3 (hepatocyte membrane), MRP2 (canalicular membrane)
- MRP2/4 (to urine)
Crigler Najjar/Hereditary Unconjugated Hyperbilirubinemia
- autosomal recessive disease, usually presents in infant
- non-hemolytic jaundice due to defective UDPGT enzyme which conjugates bilirubin in the liver, lots of unconjugated bilirubin, brain damage if untreated
Type 1 Crigler Najjar vs Type 2 Crigler Najjar
Type 1: UGT1A1 mutation, absent activity, more severe version
Type 2: UGT1A1 mutation, less activity compared to normal
Other than bilirubin conjugation, what other roles does UGT1A1 do?
metabolizes anti-cancer drugs like Ironotecan. conjugates its toxic metabolite SN38 by adding glucose = SN38 glucuronide
Kernicterus
bilirubin buildup and deposit on brain > impairs brain fxn, lead to death if severe
How do you treat Crigler Najjar syndrome?
plasmapheresis
phototherapy
Phenobarbitol (induces UGT1A1, only works on Type 2)
Liver transplant
What is the pathophysiology of Gilbert’s syndrome?
- hereditary unconjugated hyperbili w/o evidence of hemolysis or hepatitis
- UGT1A1 promoter defect = 30% UDPGT activity compared to normal
What are the symptoms of Gilbert syndrome?
Treatment?
- usually asymptomatic, mild jaundice occasionally, associated with fasting
- usually doesn’t need treatment, but avoid Irinotecan
Causes of Dubin Johnson syndrome vs. Rotor’s syndrome
DJS: MRP2 mutation (transports stuff from hepatocyte to bile)
Rotor’s: OATP1B1/B3 mutation (impairs bilirubin storage in liver)
*both conjugated hyperbilirubinemia
Symptoms of Dubin Johnson vs Rotor’s
DJS: conjugated bili + black liver due to impaired excretion of metabolites, pigment deposition
RS: conjugated bili + liver not black, usually benign
Labs in Dubin Johnson vs Rotor’s
DJS: elevated bilirubin, normal urine coproporphyrin
RS: normal total bili, elevated urine coproporphyrin
Hemochromatosis
increased iron absorption due to decreased hepcidin (which dissolves the iron transporter)
Wilson Disease
cause
symptoms
- copper accumulation in brain, liver and tissues due to ATP7B mutation
- multiple colored rings in iris/Keyser Fleischer rings, parkinson’s like symptoms, ballistic limb movements, CNS stuff
Why is ATP7B important in Wilson Disease?
transports copper into bile, if mutated copper is not excreted out of liver
-it also helps bind copper to ceruloplasmin in liver, so without it copper accumulates in the blood and becomes free radicals
What are the lab findings for Wilson disease?
- low total serum copper (due to lack of ceruloplasmin)
- high free serum copper and urine copper
How do you treat Wilson Disease?
- chelation therapy (penicillamine, trientine)
- Zn (competitive inhibitor of Cu for absorption in gut, prevents Cu from being absorbed)
- Ammonium tetrathiomolybdate (induces Cu urine excretion)
- Liver transplant
Galactosemia
Classic vs type 2
Clinical
Deficiency in GALT enzyme (classic) or Galactokinase (type 2) Classic symptoms: -Vomiting/Diarrhea after consuming milk -Enlargement of liver -Cataracts
Type 2 symptoms:
-build of galactitol (cataracts)
What is Von Gierke Disease?
Deficiency in Glucose-6 phosphatase
