Cytochrome P450

Cytochrome P450 and the Drug Response

Most drugs are cleared by CYP proteins. Drugs can increase or decrease the activity of one or more CYP enzymes, which alters the rate at which the drug is degraded and cleared from the body. This can work both ways. When a drug increases the activity of a CYP protein, CYP can render the drug ineffective, because it is cleared too quickly from the body. Alternatively, when a drug inhibits a CYP protein, CYP may not prevent the drug from accumulating to toxic levels, even to the extent of causing an overdose.

Of the several families of CYP proteins, CYP1, CYP2, CYP3 and CYP4 are the most important in terms of drug biotranformations, especially CYP3A4, which is the most prevalent CYP in the body and metabolises several drugs. CYP proteins can affect many aspects of a drug’s response in a patient, some of which are listed below.

Drug response variability

Medicines can have different responses in different people, some drugs being rendered ineffective, others causing adverse reactions. Drug variability is largely due to differences in CYP protein activity, caused by polymorphic variations between people, age or environmental factors such as diet. By far the greatest factor is genetic predisposition due to polymorphic variations, as discussed previously.

In addition, a person’s level of various CYP proteins can vary with age. For example, newborns do not express CYP1A2, making them susceptible to the toxic effects of caffeine. In recent years, various screens have become available to test a person’s level of the major CYP proteins involved in drug clearance, in order to help predict drug tolerance.

Drug-drug interactions

In addition to affecting its own rate of clearance, drugs can affect the rate of clearance of other drugs, causing drug-drug interactions. Therefore, a drug may be cleared properly from the body, but it could affect the clearance of a second drug taken at the same time by affecting its CYP clearance protein, causing the second drug to accumulate to dangerous levels. For this reason, taking different medications is strictly controlled by doctors.

Food-drug interactions

Even natural substances found in foods can affect CYP proteins, which in turn can alter drug responses. For example, grapefruit contains bioactive compounds such as bergamottin that can inhibit CYP3A4, an important CYP enzyme required to degrade several types of drugs, thereby increasing the risk of toxicity and adverse affects with those drugs. Drugs known to interact with grapefruit include statins, antiarrhythmic agents, immunosuppressive agents, and calcium channel blockers. It is generally advised that people on these types of medications avoid the consumption of grapefruit. Other bioactive foods that affect CYP3A4 enzymes include pomegranate juice and red wine, as well as St John’s wort extracts.

Drug bioactivation

Besides being degraded and cleared, some drugs can also be activated to form potent metabolites. Bioactivation occurs primarily in the liver, but can also occur in kidneys, skin, lung and intestine. For example, it is estimated that about 3-4% of ingested codeine (an opium alkaloid) can be converted in the liver to morphine, providing much of the drug’s analgesic effect.

Drug Testing

New drugs coming onto the market must be tested against cytochrome P450 enzymes in several ways.

· Clearance rate of a drug must be determined for accurate dosage determination. If a drug is extensively metabolised after oral administration by liver enzymes, rendering it inactive before it can be circulated (high first-pass effect), then it may be tested for administration by other routes, such as by injection.

· Bioactivation of a drug must be determined to avoid undesired side effects that are only seen after transformation by the liver. Frequently, drugs that seem desirable during development will be rendered toxic after a liver enzyme assay. However, sometimes bioactivation may be important for the efficacy of a drug, such as with the conversion of codeine to morphine.

· Activation/inhibition of CYP proteins by a drug need to be determined in order to predict drug-drug interactions. Drugs are tested to see whether they affect the activity of any CYP proteins. If they do, they must not be given in conjunction with drugs known to be cleared by those CYP proteins.

Detailed information exists regarding the metabolism and clearance of drugs by specific CYP proteins, which is useful for predicting potential drug interactions. Some useful websites are:

Table and data of human CYP proteins: http://drnelson.utmem.edu/hum.html

Drug interactions: http://medicine.iupui.edu/flockhart/

Table of CYP protein alleles: http://www.cypalleles.ki.se/cyp2c19.htm

Tables of metabolism, induction and inhibition of various drugs, CYP proteins and foods: http://www.edhayes.com/startp450.html