Phase I Reactions: Cytochrome P450 System

Cytochrome P450 System - Detox Dynamo

• Family of heme-containing monooxygenases; key players in Phase I detoxification.
• Location: Primarily smooth endoplasmic reticulum (SER) of hepatocytes; also extrahepatic (gut, lungs, kidney).
• Core Reaction: $RH + O_2 + NADPH + H^+ \rightarrow ROH + H_2O + NADP^+$
  • Adds or unmasks polar groups (e.g., -OH, -NH2, -SH).
• Function: Metabolizes diverse xenobiotics (drugs, carcinogens) & endogenous molecules (steroids, prostaglandins).
• Named for 450 nm light absorption peak when CO-bound.

⭐ CYP3A4 is the most abundant CYP isoform in the human liver, responsible for metabolizing approximately 50% of clinically used drugs.

Cytochrome P450 System - Metabolic Makeover

• Location & Structure: Predominantly in liver smooth endoplasmic reticulum; heme-containing monooxygenases.
• Function: Metabolize diverse substrates: xenobiotics (drugs, carcinogens, pollutants) & endogenous compounds (steroids, fatty acids, prostaglandins).
• Nomenclature: CYP + Arabic numeral (family) + capital letter (subfamily) + Arabic numeral (isoform). E.g., CYP3A4 is a major drug-metabolizing enzyme.

Principal Reactions (Phase I):

• Oxidation (most common):
  • Hydroxylation: $R-H + O_2 + NADPH + H^+ \rightarrow R-OH + H_2O + NADP^+$
  • N-dealkylation, O-dealkylation, S-dealkylation
  • Epoxidation, N-oxidation, S-oxidation
• Reduction (e.g., azo, nitro reduction)
• Hydrolysis (less frequent for P450s)

Catalytic Cycle:

⭐ The CYP450 catalytic cycle critically depends on NADPH-cytochrome P450 reductase for the transfer of electrons from NADPH to the P450 enzyme.

Cytochrome P450 System - Induction & Inhibition Show

• Enzyme Induction:
  • Process: ↑ synthesis of CYP450 enzymes.
  • Leads to: ↑ drug metabolism rate.
  • Clinical effect: ↓ drug efficacy or ↑ production of toxic metabolites.
• Enzyme Inhibition:
  • Process: ↓ activity of CYP450 enzymes (competitive or non-competitive).
  • Leads to: ↓ drug metabolism rate.
  • Clinical effect: ↑ plasma drug concentration → ↑ risk of drug toxicity.

Cytochrome P450 System - Genes & Drugs

• Key Gene Families: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5.
• Genetic Polymorphisms:
  • Cause inter-individual variations in drug metabolism.
  • Phenotypes: Poor Metabolizers (PMs), Intermediate (IMs), Extensive (EMs), Ultra-rapid Metabolizers (UMs).
  • PMs: ↑ risk of drug toxicity; UMs: may experience therapeutic failure with standard doses.
• Common Inducers (↓ drug efficacy):
  • Rifampicin, Carbamazepine, Phenytoin, Phenobarbital, St. John’s Wort, Chronic alcohol use, Smoking.
• Common Inhibitors (↑ drug toxicity):
  • Azole antifungals (e.g., Ketoconazole), Macrolides (e.g., Erythromycin), Grapefruit juice, Cimetidine, SSRIs (e.g., Fluoxetine), Protease inhibitors.

⭐ CYP2D6 polymorphism significantly affects the metabolism of codeine to morphine, impacting analgesic efficacy. Poor metabolizers may experience little to no pain relief, while ultra-rapid metabolizers may have increased adverse effects due to rapid morphine conversion.

High‑Yield Points - ⚡ Biggest Takeaways

• CYP450 enzymes: Located in liver smooth ER; are heme-containing monooxygenases.
• Primary role: Catalyze Phase I reactions (oxidation, reduction, hydrolysis) for drug metabolism.
• CYP3A4: Most abundant isoform, metabolizes ~50% of clinically used drugs.
• Inducers (e.g., Rifampicin, Phenobarbital) accelerate metabolism, potentially ↓ drug efficacy.
• Inhibitors (e.g., Ketoconazole, Grapefruit juice) slow metabolism, potentially ↑ drug toxicity.
• Genetic polymorphisms in CYP genes cause significant inter-individual variations in drug response.