In the treatment of mental disorders (such as anxiety disorders and depression) medication is often used. Many of these drugs and many other external substances are metabolized (processed) by the enzymes of the cytochrome P450 system. With a DNA defect on cytochrome P450 genes, certain drugs and substances can not be metabolized properly. The side effects can be so serious that the user can develop a psychosis based on medication poisoning – a toxic psychosis or a delirium or akathisia. Toxicity due to psychoactive medication can lead to vague complaints of restlessness, anxiety, nightmares up to a state of fully developed akathisia with extreme violence, murder, manslaughter or suicide.
The DNA that codes for the enzymes that influence the conversion of drugs is called Cytochrome P450.
Enzymes are proteins that are involved in reactions in biological processes and act as catalysts. P450 enzymes are found everywhere in the animal and plant kingdom. They metabolize a large number of substances within the body, as well as substances from outside the body, such as medication. P450 enzymes are found mainly in the liver, but are also present in the intestines, the lungs, the brain and the kidneys.
The genes encoding the P450 enzyme system consist of 18 families and 44 subfamilies. A family name is indicated by a figure, for example CYP2, then followed by the subfamily with a capital letter, for example CYP2D and finally the individual gene or enzyme with a number again: CYP2D6.
Each individual has two copies of each gene, one inherited from each parent. The variant form of a copy is called an allele. The alleles are indicated in the nomenclature with an asterisk * and a number, for example 1, separated by a slash /. If someone inherits the same allele from his father and mother, this can for example be CYP2D6 *1/*1. If someone has received two different alleles from their parents, it could be CYP2D6 *1/*3 for example. The alleles that are considered normal (standard) are called “wild type” and are most common in the general population. Every allele, other than the wild type, is called “variant” or “polymorphism”. Someone with normal metabolism is called an “Extensive Metabolizer” or “EM”. Such a person has two copies of the wild type alleles. Polymorphism occurs when a variant allele replaces one or both wild type alleles. In general, variant alleles encode a Cytochrome P450 enzyme that has reduced or no activity.
Individuals with two copies of a defective allele are called “Poor Metabolizers (PM)”, while those with one normal allele (wild type) and one defective allele or two partially functioning alleles are referred to as “Intermediate Metabolizers (IM)” and have a reduced metabolic activity. There are also people who inherit multiple copies of wild type alleles and therefore the gene produces more enzymes. These people are called “Ultra-rapid Metabolizer (UM)” or super-fast metabolisers.
The efficacy of the Cytochrome P450 enzyme system is genetically determined and is also influenced by intrinsic factors such as age, gender, comorbidity (other diseases present) and extrinsic factors such as diet, smoking, substance abuse (drugs, caffeine, alcohol) and medicine-interactions (comedication).
Medication can be metabolized by a P450 enzyme, i.e. the enzyme uses the medication as “substrate” = S (substance to be converted).
In addition, a drug can be metabolized by an enzyme while that medication inhibits another enzyme = Inh. For example, the drug Paroxetine is metabolized by CYP2D6, but inhibits enzymes produced by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4
Substrate & Inhibitor
A drug can be both substrate and inhibitor for a certain enzyme. Advil is metabolised by enzymes of CYP2C8, CYP2C9 and CYP2C19, but at the same time inhibits the functionality of the enzymes of CYP2C8 and CYP2C9.
These are called gene-drug interactions. When medication is combined, drug-drug interactions can arise. These interactions can cause problems in the conversion of medication, which may increase the amount of medication in the blood (blood levels). With the rise of blood levels, the chance of side effects also increases. An increase in interactions leads to a darker color in the tables.