Cytochrome P450 (CYP)

CYP450

Cytochromes P450s are a family of enzymes that are of paramount importance in drug biotransformation. The most important isoenzymes for drug metabolism are:

  • CYP1A1, CYP1A2
  • CYP2B6
  • CYP2C9, CYP2C19
  • CYP2D6
  • CYP2E1
  • CYP3A4, CYP3A5 and CYP3A7

The number after the abbreviation CYP stands for the family, the following letter for the subfamily and the last number for the individual enzyme. The cytochromes are mainly localized in the liver, but they are also found in other organs, especially in the intestine. They play an important role in first-pass metabolism. Some family members are also involved in the metabolism of endogenous molecules such as steroids, bile acids, fatty acids, eicosanides, and fat-soluble vitamins.

Chemical reactions

CYPs contain a molecule of heme in the protein as a cofactor. With the central iron atom, they bind and activate oxygen, transferring one atom of oxygen each to the substrate and a newly formed water molecule. The enzymes are therefore called monooxygenases. They catalyze the following general reaction, where R-H stands for the substrate: R-H + O2 + NADPH + H+ R-OH + H2O + NADP+ This reaction corresponds to a hydroxylation. An alcohol is formed or, in the case of aromatic hydroxylation, a phenol. For example, the analgesic ibuprofen is hydroxylated by CYP2C9: Other reactions include epoxidation, dealkylation, deamination, and oxidation. Changing the chemical structure of a molecule can lead to activation or inactivation. Some toxins – such as aflatoxin B1 – are prodrugs and are first toxified by cytochromes.

Drug interactions

CYP substrates are susceptible to drug-drug interactions with inhibitors or inducers of metabolic enzymes. Particular caution should be exercised with agents that have a narrow therapeutic range, high toxicity, and drugs that prolong the QT interval.

CYP Inhibitors

CYP inhibitors are agents or other substances that reduce the activity of CYP isozymes. This leads, for example, to a reduction in the inactivation of an active ingredient. This increases the risk of adverse effects. If CYP450 isozymes are involved in the activation of a prodrug, inhibition results in less active drug. A loss of efficacy may occur. Well-known CYP inhibitors include the azole antifungals, macrolides (commonly: clarithromycin), and HIV protease inhibitors.

CYP Inducers

CYP inducers increase enzyme activity by stimulating protein synthesis. The effect occurs with a time delay. This results in increased metabolism of CYP substrates. This results, for example, in increased degradation of ethinyl estradiol, the estrogen in many hormonal contraceptives, leading to pregnancy. Typical examples include the rifamycins such as rifampicin, the barbiturates, St. John’s wort, and antiepileptic drugs such as carbamazepine.

Pharmacokinetic boosters

The drug-drug interactions described above are not necessarily adverse. Pharmacokinetic boosters such as ritonavir or cobicistat are combined with CYP substrates to slow their degradation and increase bioavailability. The boosters are usually CYP inhibitors.

Pharmacogenetics

The enzyme activity of cytochromes varies interindividually due to genetics. This is particularly true for CYP2D6 and CYP2C19. Fast, slow, and normal metabolizers exist in the population. For CYP2D6, up to 15% of the population are slow metabolizers (!) A typical CYP2D6 substrate is the antitussive dextromethorphan. A known substrate of CYP2C19 is clopidogrel, which is activated by this enzyme. The effect on pharmacokinetics is comparable to CYP inhibition or CYP induction. Slow metabolizers have an increased risk of adverse effects, and rapid metabolizers may fail to produce the effect of a drug. Today, it is possible to easily determine the genetic profile with laboratory analysis and to individualize therapies. As a result, side effects can be avoided.

Response to drug interactions

  • Assessment of clinical relevance, e.g., using the SmPC or with applications.
  • Temporary or permanent discontinuation of a medication.
  • Change of a drug
  • Dose adjustments

Information sources

Reviews of key substrates, inhibitors, and inducers:

  • Kisch.ch (Ali Sigaroudi, Hans Vollbrecht): http://kisch.ch (very comprehensive, with registration).
  • Flockhart Table (David Flockhart): https://drug-interactions.medicine.iu.edu/Main-Table.aspx

Detailed information can also be found in the drug factsheet or in the scientific literature.