Enzyme induction and inhibition
Enzyme inhibition can refer to
- the inhibition of the expression of the enzyme by another molecule
- interference at the enzyme-level, basically with how the enzyme works. This can be competitive inhibition, uncompetitive inhibition, non-competitive inhibition or partially competitive inhibition.
If the molecule induces enzymes that are responsible for its own metabolism, this is called auto-induction (or auto-inhibition if there is inhibition). These processes are particular forms of gene expression regulation.
In the late 1950s and early 1960s, the French molecular biologists François Jacob and Jacques Monod became the first to explain enzyme induction, in the context of the lac operon of Escherichia coli. In the absence of lactose, the constitutively expressed lac repressor protein binds to the operator region of the DNA and prevents the transcription of the operon genes. When present, lactose binds to the lac repressor, causing it to separate from the DNA and thereby enabling transcription to occur. Monod and Jacob generated this theory following 15 years of work by them and others (including Joshua Lederberg), partially as an explanation for Monod's observation of diauxie. Previously, Monod had hypothesized that enzymes could physically adapt themselves to new substrates; a series of experiments by him, Jacob, and Arthur Pardee eventually demonstrated this to be incorrect and led them to the modern theory, for which he and Jacob shared the 1965 Nobel Prize in Physiology or Medicine (together with André Lwoff).
One class of key enzymes for drug metabolism belong to the family of cytochrome P450 oxidases, like CYP3A4, CYP2D6, CYP1A2, etc. They reside in the endoplasmatic reticulum (ER), and prolonged usage of substances inducing enzymes here may cause proliferation of the ER. They are responsible for phase I reactions.
Enzyme induction and inhibition are important processes to take in account when using drugs of vital importance to the patient, drugs with important side effects and drugs with small therapeutic windows, but any drug may be subject to an altered plasma concentration due to altered drug metabolism.
A classical example includes anti-epileptic drugs. Phenytoin, for example, induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Substrates for the latter may be drugs with critical dosage, like amiodarone or carbamazepine, whose blood plasma concentration may decrease because of enzyme induction.
Not only drugs may alter drug metabolism. Tobacco smoking induces CYP1A2 (example substrates are clozapine/olanzapine), Saint-John's wort (a common herbal remedy) induces CYP3A4, which is inhibited by grapefruit juice. There are known examples of situations where this may produce clinical effects.
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