Genomics of Drug Response

Genetic variation in genes encoding proteins involved in a drug’s pharmacokinetics can alter how a drug is metabolized. If a drug is metabolized too quickly, it might not be as effective. Alternatively, if the drug is metabolized too slowly, it may build up in the body and cause dangerous side effects.

Photo credit: US National Library of Medicine

Changes to your DNA can be small, like single nucleotide polymorphisms (SNPs), where a single letter is changed to a different letter. Or they can be a lot bigger where many DNA letters are added, deleted or rearranged

The CYP2C19 gene provides instructions for making an enzyme that is found primarily in liver cells in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.

Cytochrome P450 family enzymes produced from cytochrome P450 genes are involved in the formation and breakdown (metabolism) of various molecules and chemicals within cells.

CYP2C19 enzyme is involved in the metabolism of many drugs, changes to the enzyme can have wide-ranging effects. Drugs that are affected by CYP2C19 gene polymorphisms include proton pump inhibitors, used to treat stomach ulcers and other conditions; antidepressants, used to treat psychiatric disorders; anticonvulsants, used to treat seizure disorders; hypnotics and sedatives, used as sleep aids; antimalarial drugs, used to prevent malarial infections; and antiretroviral drugs, used to prevent viruses from replicating.

CYP2D6 gene localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs, like antidepressants, antipsychotics, analgesics & others.

 

For example, it converts the painkiller codeine into its active form, morphine. There are more than 160 versions of the CYP2D6 gene. Many vary by only a single difference in their DNA sequence. Others have larger changes. Most of these variants don’t affect how people respond to the drug.

 

Typically, people have two copies of each gene. However, some people have hundreds or even thousands of copies of the CYP2D6 gene. Those with extra copies produce too much of the CYP2D6 enzyme and process the drug very fast. As a result, their bodies may convert codeine to morphine so quickly and completely that a standard dose can be an overdose. In contrast, some variants of CYP2D6 create an enzyme that doesn’t work. People with these variants process codeine slowly, if at all, leading to little, if any, pain relief. For them, doctors can prescribe a different drug.

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