Biotransformation

Question 1

Biotransformation

Answer 1

• chemical modification made by organisms on a chemical compound
• make non-polar compounds polar ⇒ can be excreted rather than reabsorbed
• intermediary metabolism

Question 2

Drug metabolism

Answer 2

• xenobiotic metabolism
• often converts lipophilic compounds into more hydrophilic
• rate of metabolism determines the duration and intensity of a drug’s pharmacological action

Question 3

Phase 1 metabolism

Answer 3

• may occur by oxidation, reduction, hydrolysis, cyclization, decyclization etc
• often in liver
• oxidative reactions involve cytochrome P450 monooxygenase, NADPH and oxygen
• purpose is to make compound more water soluble

Question 4

CYP1

Answer 4

• CYP1A1, CYP1A2, CYP1B1
• inducers: methylcholantrene, dioxin derivatives, environmental pollution, cigarette smoke ⇒ bronchial carcinoma
• substrates: polycyclic aromatic hydrocarbons PAH, medicines(teophyllin, caffeine, phenacentine)

Question 5

CYP-2

Answer 5

• inducers: phenobarbital, ethanol, acetone, diazepam derivatives
• CYP2A ⇒ synthesis of steroids and testosterone
• CYP2B ⇒ progesterone, Vitamin D3, antiepileptics
• CYP2C ⇒ mephenytoin-antiepileptics
• CYP2D ⇒ metabolism of antidepressants, beta-blockers, antihypertensives
• CYP2E ⇒ metabolism of ethanol acetone; associated with diabetes mellitus, starvation periods

Question 6

Cytochrome P450 system

Answer 6

• RH + O2 + NADPH + H+ ⇒ ROH + H2O + NADP+
• contain heme cofactor (hemoprotein)
• genes mainly expressed in liver, lungs, intestines, skin and kidneys
• drugs absorbed from GI ⇒ portal vein ⇒ liver

Question 7

CYP-3

Answer 7

• inducers: steroids- oral contraceptives, PCN

- substrates: antibiotics, nifedipine, cyclosporine

Question 8

CYP-4

Answer 8

• inducers: clofibrate

- substrates: fatty acids, eicosanoids

Question 9

Phase 2 metabolism

Answer 9

• conjugation

- joining the compound with another molecule such as glucuronic acid

Question 10

Glucuronidation

Answer 10

• enzyme catalyzing: UDP glucuronosyl transferase
• transfer of glucuronic acid from UDPGA to substrate that contain oxygen, nitrogen, sulfur or carboxyl functional group.
  ⇒ more polar glucuronide and more easily excreted than the substrate
• UGT’s activate: morphine, bile acids, steroids, retinoids, PAH’s

Question 11

Morphine

Answer 11

• 40-50% metabolized in first pass through liver
• 87% excreted in urine within 72h
• metabolized into M3G and M6G via glucuronidation by UGT2B7
• 60%⇒ M3G ⇒ no opoid receptor binding, no analgesic effect
• 6-10%⇒ M6G ⇒ binds to u-receptors
• metabolized in liver, brain, kidney

Question 12

Hyperbilirubinemias

Answer 12

• breakdown of heme ⇒ bilirubin ⇒ glucuronidation ⇒ Bilirubin diglucuronide ⇒ excreted by liver in bile
• intestinal bacteria deconjugate ⇒ urobilinogens ⇒ some absorbed and goes to kidneys and urine/ some down digestive tract as stercobilinogen⇒ stercobilin

Question 13

Gilberts syndrome

Answer 13

• unconjugated hyperbilirubineamia, hereditary disease
• increased bilirubin
• symptom: jaundice, increased unconjugated bilirubin in blood
• cause: reduced activity of UGT, SNP (point mutation)
• treatment: phenobarbital

Question 14

Crigler-Najjar syndrome

Answer 14

• unconjugated hyperbilirubinemia
• cause: early stop codon in UGT genes
• very rare
• symptom: brain damage in infant

Question 15

Conjugated hyperbilirubinemias

Answer 15

1. Dubin Johnson syndrome
2. Rotor syndrome
   - caused by problem with transport out of liver via MRP2
   - defect in gene of this transporter, build-up of conjugated bilirubin in blood ⇒ jaundice

Question 16

Sulfation by PAPS

Answer 16

3-hydroxy-coumarin + PAPS ⇒ 3-hydroxy-coumarin-suphate + AMP-P

• method of conjugation
• sulfotransferases

Question 17

GSH conjugation

Answer 17

• by GSH transferases
• Glutathione is a tripeptide (Glu-Cys-Gly)
• is seen in biotransformation of Paracetamol ⇒ phase 1 reaction with CYP2E1 ⇒ GSH transferase add Glutathione in phase 2 reaction ⇒ Glu and Gly residues removed by hydrolysis ⇒ Acetyl-CoA added ⇒ mercapturic acid