Psychopharmacology 23

The enzyme CYP1A2 is involved in the metabolism of which of the following?


Cytochrome P450 system


Some users have found this section too complicated. Don't panic, simply learning the inducers and inhibitors, and the following key facts should be enough to get you by:-

  • CYP2D6 shows the largest phenotypic variation amongst the cytochromes
  • CYP1A2 is involved in metabolism of clozapine. Tobacco induces CYP1A2 and so lower clozapine levels. Grapefruit juice inhibits CYP1A2 and therefore can increase clozapine levels.
  • Grapefruit juice inhibits CYP3A4 and CYP1A2

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The Cytochrome P450 system is an evolved mechanism that deals with exogenous toxins. The system comprises of about fifty separate enzymes. The system is essential in the metabolism of drugs.

Do not be confused by the name, The P450 part relates to the wavelength of light it absorbs. 

The enzymes are located on the endoplastic reticulum of cells and are mainly found in the liver and small intestine.

The Cytochrome system metabolizes drugs by altering the functional groups on the parent molecule (e.g. Oxidation). Drug interactions involving the system generally result from one of two processes, enzyme induction, or enzyme inhibition.

Notable inducers of the system include: - smoking, alcohol, barbiturates, carbamazepine, Phenytoin, and St John's Wort.

Notable inhibitors include: - chlorpromazine, SSRI's, and grapefruit juice.
The two main isoforms to be aware of are CYP2D6 and CYP3A. 

CYP2D6 is important as it exhibits genetic polymorphism (it varies in its expression from person to person). Caucasians show less activity of CYP2D6 (6-10% poor metabolisers) than their Asian (2% poor metabolisers) counterparts. In blacks, the frequency of poor metabolizers is greater than for whites. This is also important when the effect of a drug relies on an active metabolite as in the case of codeine. CYP2D6 is not really involved in induction interactions but is inhibited by SSRI's particularly paroxetine. 

The CYP3A subfamily is the most abundant. They are most commonly involved in interactions involving induction and inhibition. Grapefruit juice specifically inhibits CYP 3A4. Drugs metabolised by this enzyme include; carbamazepine, diazepam, sertraline, buspirone. Grapefruit juice also inhibits CYP 1A2 causing an increase in clozapine levels. Tobacco smoking causes an induction of CYP 1A2.