Mechanism of Enzyme Induction and Enzyme Inhibition

PART I — ENZYME INDUCTION

Definition

Mechanism

Step 1 — Binding to a Nuclear Receptor

Step 2 — Receptor Activation and Heterodimerization

• For AHR: The ligand-bound AHR translocates to the nucleus, dimerizes with its nuclear partner (ARNT), and binds to xenobiotic response elements (XREs) upstream of target CYP genes (CYP1A1, CYP1A2, CYP1B1).
• For Type 2 nuclear receptors (PXR, CAR): After ligand binding, the receptor heterodimerizes with the Retinoid X Receptor (RXR), forming a PXR–RXR (or CAR–RXR) complex that binds to drug-response elements on the promoter region of target genes.

Step 3 — Recruitment of Coactivators and Transcription

Step 4 — Increased Enzyme Synthesis

Temporal Course

Clinical Consequences of Enzyme Induction

Common Enzyme Inducers (CYP3A4)

PART II — ENZYME INHIBITION

Definition

"Inhibition of drug metabolism is the most important mechanism for drug interactions because it can lead to an increase in plasma drug concentration, enhanced drug response, and toxicity." — Dermatology 5e, p. 131

Temporal Course

Types of Enzyme Inhibition

1. Competitive (Reversible) Inhibition

• The inhibitor competes with the substrate for the same active site of the CYP enzyme.
• Drugs such as macrolide antibiotics (erythromycin, clarithromycin), cimetidine, and ketoconazole bind tightly to the heme iron of the CYP isoenzyme.
• As inhibitor concentration increases, the degree of isoenzyme saturation increases → at full saturation, the patient effectively behaves as a "poor metabolizer" of all substrates for that CYP.
• This is reversible — removing the inhibitor restores enzyme function.

2. Non-competitive Inhibition

• The inhibitor binds at a different site from the substrate (allosteric site), causing a conformational change in the enzyme.
• The inhibitor can bind whether or not the substrate is present.
• Maximum reaction velocity (Vmax) is reduced; Km is unchanged.
• Some drugs inhibit CYP reactions for which they are not themselves substrates — e.g., ketoconazole inhibits multiple CYPs beyond the one that metabolizes it.

3. Mechanism-Based (Irreversible / Suicide) Inhibition

• Also called "suicide inhibition" or time-dependent inhibition.
• The inhibitor (or its reactive metabolite, generated by the CYP itself) covalently and irreversibly modifies the enzyme, permanently destroying its catalytic activity.
• Recovery requires de novo synthesis of new CYP enzyme (days).
• This results in destruction of the enzyme and release of heme, which is then catabolized by heme oxygenase → reduction in the free heme pool → secondary induction of δ-aminolevulinic acid synthase (ALAS1) — clinically relevant in porphyria triggers.

• Erythromycin and clarithromycin form nitroso metabolites that covalently bind CYP3A4
• Grapefruit juice furanocoumarins irreversibly inhibit intestinal CYP3A4

4. Product Inhibition / Competition for Phase II Pathways

• Competition for phase II conjugation pathways (glucuronidation, sulfation) → unconjugated drug is shunted back toward CYP oxidation → apparent CYP inhibition in high-load settings.
• Example: Zidovudine + phenytoin compete for glucuronidation → increased CYP-dependent metabolism → lowers the dose threshold for acetaminophen-induced hepatotoxicity.

Clinical Consequences of Enzyme Inhibition

Key CYP3A4 Inhibitors

Summary Comparison Table

Clinical Significance (Exam Pointer)

• ~56% of drugs associated with adverse drug reactions (ADRs) are substrates for xenobiotic-metabolizing enzymes.
• ADRs from enzyme interactions cost an estimated $100 billion annually and cause over 100,000 deaths per year in the United States.
• Prior to filing a New Drug Application (NDA), identifying which CYPs metabolize a new drug and whether it is an inducer or inhibitor is now mandatory.