Lecture 19 Biotransformation IV
Induction/Inhibition of enzyme activity affects drug biotransformation capacity.
•Important for drugs with narrow therapeutic index (e.g. Warfarin (blood thinner),
CYP3A4/1A2/2E1 are inducible
Potent inducers of drug-metabolizing enzymes
•TCDD (environmental toxicant)
•Indo Carbazole (cabbage family)
•benzo[α]pyrene (in cigarette smoke)
Benzo[α]pyrene induces its own metabolism.
Metabolism of inducer is accelerated at high doses.
Cigarette smoke (contains BP) induces CYP1A1 activity
CYP1A1 activity in human placenta is high in smokers.
The process of enzyme induction refers to increase in gene transcription.
How induction works:
1. TCDD (inducer) enters cell
2. TCDD binds to AHR (aromatic hydrocarbon receptor) complex with high affinity.
3. TCDD-AHR complex transformation/translocation to nucleus.
4. Another receptor ARNT binds: ARNT binds to complex, which then binds to
promoter region of DNA
5. Regulation of specific mRNAs to produce P450 or phase II enzymes
6. Increased biotransformation of drug, environmental chemistry.
Phenobarbital decreases plasma [dicumarol], efficacy
•Dicumarol (blood thinner)
•Phenobarbital (CYP inducer, sedative)
•Therapeutic efficacy affected with dose of Phenobarbital
•Drug-drug interaction: one drug induces the metabolism of another drug.
Hepatic toxicity of acetaminophen is decreased by inhibitors of the Constitutive
Androstone Receptor (CAR), the receptor that mediates P450 induction by Phenobarbital
and related compounds.
CAR mediates CYP induction by a herbal preparation.
Does physician know non-prescription substances patients are taking?
•Indinavir (treats HIV) and St. John’s Wort
oSt. John’s Wort decreases the bioavailability of Indinavir.