Microsomal Enzyme Induction

MICROSOMAL ENZYME INDUCTION

Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of microsomal enzyme protein, especially cytochrome P-450 and UGTs. As a result rate of metabolism of inducing drug itself and/or other drugs is increased.

Different inducers are relatively selective for certain cytochrome P-450 isoenzyme families, e.g.:

Anticonvulsants (phenobarbitone, phenytoin, carbamazepine), rifampin, glucocorticoids induce CYP3A isoenzymes.
Phenobarbitone also induces CYP2B1 and rifampin also induces CYP2D6.
Isoniazid and chronic alcohol consumption induce CYP2E1.
Polycyclic hydrocarbons like 3-methylcholanthrene and benzopyrene found in cigarette smoke, charcoalbroiled meat, omeprazole and industrial pollutants induce CYP1A isoenzymes.
Other important enzyme inducers are: phenylbutazone, griseofulvin, DDT.

Since different CYP isoenzymes are involved in the metabolism of different drugs, every inducer increases biotransformation of certain drugs but not that of others. However, phenobarbitone like inducers of CYP3A and CYP2D6 affect the metabolism of a large number of drugs, because these isoenzymes act on many drugs. On the other hand induction by polycyclic hydrocarbons is limited to few drugs (like theophylline, phenacetin) because CYP1A isoenzyme metabolizes only few drugs.

Induction involves microsomal enzymes in liver as well as other organs and increases the rate of metabolism by 2–4 fold. Induction takes 4–14 days to reach its peak and is maintained till the inducing agent is being given. Thereafter the enzymes return to their original value over 1–3 weeks.

Consequences of Microsomal Enzyme Induction

Decreased intensity and/or duration of action of drugs that are inactivated by metabolism, e.g. failure of contraception with oral contraceptives.
Increased intensity of action of drugs that are activated by metabolism. Acute paracetamol toxicity is due to one of its metabolites toxicity occurs at lower doses in patients receiving enzyme inducers.
Tolerance, if the drug induces its own metabolism (autoinduction), e.g. carbamazepine, rifampin.
Some endogenous substrates (steroids, bilirubin) are also metabolized faster.
Precipitation of acute intermittent porphyria: enzyme induction increases porphyrin synthesis by derepressing δ-aminolevulenic acid synthetase.
Intermittent use of an inducer may interfere with adjustment of dose of another drug prescribed on regular basis, e.g. oral anticoagulants, oral hypoglycaemics, antiepileptics, antihypertensives.
Interference with chronic toxicity testing in animals.

Drugs whose metabolism is significantly affected by enzyme induction are: phenytoin, warfarin, tolbutamide, imipramine, oral contraceptives, chloramphenicol, doxycycline, theophylline, griseofulvin, phenylbutazone.

Possible Uses of Enzyme Induction

Congenital nonhaemolytic jaundice: It is due to deficient glucuronidation of bilirubin; phenobarbitone hastens clearance of jaundice.
Cushing’s syndrome: phenytoin may reduce the manifestations by enhancing degradation of adrenal steroids which are produced in excess.
Chronic poisonings: by faster metabolism of the accumulated poisonous substance.
Liver disease.

Reference: Essential of Medical Pharmacology KD Tripathi.