Metabolism and Pharmacogenomics

• All CYPs have a heme group in the central active site which is involved in oxygen activation
• The substrate of CYPs are oxidised to release -OH and oxygen is split to produce water
• The polypeptide chain differs between CYPs and controls substrate specificity
• Each CYP is encoded by a different gene
• Variations in the amino acid sequence of CYPs may influence enzyme function
• CYPs are named based on their genetic sequences
• CYP = cytochrome P450
• The first number of CYPs designates the family
• The letter of CYPs designates the sub-family
• The last number of CYPs designates the specific gene/enzyme
• When italicised, the CYP name is referring to the gene that codes for the cytochrome P450
• When not italicised, the CYP name is referring to the mRNA or protein product of the cytochrome P450 gene
• CYP3A4 metabolises the greatest proportion of drugs
• Properties of CYPs that influence therapy

  • They are readily inhibited
  • Some are inducible
  • Subject to extensive pharmacogenetic variability
  • Induction of CYPs can increase metabolic activation of pro-drugs or toxicants
• Exposure to drugs/chemicals can increase the production of CYPs in the liver
• Individuals metabolise drugs differently
• CYP3A4 is a major CYP in the human liver, as well as in the intestine and some other tissues
• Many drugs are metabolised by CYP3A4
• Drugs metabolised by CYP3A4

  • Statins
  • HIV protease inhibitors
  • benzodiazepines
  • calcium channel blockers
• CYP3A4 is readily inhibited by pharmacokinetic drug interactions
• Ketoconazole is the greatest inhibitor of CYP3A4
• Rifampicin is the greatest inducer of CYP3A4
•  the benzodiazepine triazolam is a CYP3A4 substrate
• Diltiazem inhibits CYP3A4 clearance of triazolam, therefore increasing its half life and concentration in the blood
• Grapefruit juice was found to increase drug absorption and bioavailability of drugs, increasing maximal drug concentration consistent with hepatic CYP3A4 inhibition
• grapefruit juice won't affect maximal drug concentration if the drug is administered intravenously because the drug bypasses CYP3A4 in enterocytes
• grapefruit juice inhibits intestinal CYP3A4
• CYP3A4 genes are activated by exposure to drugs and chemicals
• Induction of CYPs

  1. The drug/chemical enters the cell
  2. The drug/chemical either enters the nucleus and binds PXR or binds CAR which enters the nucleus
  3. In the nucleus, the drug complex forms a heterodimer with RXR
  4. The heterodimer binds PXR-response elements at the 5' flanking region of the target gene
  5. This increases transcription of the CYP
• XREM and PBREM are gene elements
• XREM is activated by PXR
• PBREM is activated by CAR
• St John's Wort as a CYP3A4 inductor

  • Increases CYP3A4 in the liver
  • Increased clearance of drugs metabolised by CYP3A4
  • Decreased systemic exposure
  • Diminished therapeutic effects
• debrisoquine hydroxydebrisoquine

  • Found that optimal dosage varied greatly for individuals
  • Variation between excretion of the drug and its metabolite
• Metabolite analysis showed that there were two distinct populations of debrisoquine hydroxydebrisoquine metabolisers
• Found that there is great variation in CYP2D6 within the population, with some people lacking the enzyme entirely
• CYP2D6*1/*1 = normal
• CYP2D6*1/*3 = decreased function
• Ultrarapid metabolisers would have gene duplication, e.g. *1/*1x2
• There are many SNIPs in the CYP2D6 gene