Genetics of CYP2D6 and CYP2C19 Drug Response
Many prescribed drugs are metabolized, or broken down, by enzymes that belong to a group called CYP450 enzymes. There are two members of the CYP450 family – called CYP2D6 and CYP2C19 – that seem to be especially important in metabolizing many antidepressants, antipsychotics, and an ADHD drug called atomoxetine.
The CYP2D6 and CYP2C19 enzymes are made by instructions coded within our genes. We all have genes that don't work in the usual way. This happens because we inherit small variations in our instruction codes that make us unique.
CYP2D6
CYP2C19
Metabolizer Status
Inheritance
CYP2D6
There are at least 70 different variants of the CYP2D6 gene. The "normal" forms of the 2D6 gene are called CYP2D6*1, or CYP2D6*2. Some of the most common variants are listed in the table below. The variants that aren't in the table are less common.
Percent of People Who Have CYP2D6 Variants Based on Race/Ethnicity
| Variant | Caucasian/White | African/Black | Asian |
| CYP2D6*2 | 25% to 35% | 2% to 45% | 9% to 20% |
| CYP2D6*2XN (amplification) | 1% to 5% | 2% | Up to 2% |
| CYP2D6*3 | 2% | Rare | Rare |
| CYP2D6*4 | 12% to 21% | 2% | 1% |
| CYP2D6*5 | 2% to 7% | 4% | 6% |
| CYP2D6*6 | About 1% | Rare | Rare |
| CYP2D6*9 | About 2% | Rare | Up to 3% |
| CYP2D6*10 | 1% to 2% | 6% | 51% |
| CYP2D6*17 | Rare | Up to 34% | Rare |
| CYP2D6*29 | Rare | Up to 20% in some parts of Africa | Unknown |
| CYP2D6*41A | 20% | 3% to 8% | 2% to 11% |
CYP2C19
There are at least 20 different variants of the 2C19 gene. The "normal" form of the 2C19 gene is called CYP2C19*1. The two most common variants are 2C19*2 and 2C19*3. Other variants are usually found in less than 2% of people.
Percent of People Who Have CYP2C19 Variants Based on Race/Ethnicity
| Variant | Caucasian/White | African/Black | Asian |
| 2C19*2 | 13% to 15% | 16% to 18% | About 30% |
| 2C19*3 | Less than 1% | Less than 1% | 5% to 10% |
Metabolizer Status
Genes come in pairs. How well your CYP2D6 and CYP2C19 enzymes work depends on your particular combination of gene variants. Extensive (normal) metabolizers have two genes that work normally. Poor metabolizers have variants in both of their genes that cause neither gene to work normally. Ultrarapid metabolizers have extra copies of these genes so they make more enzyme than normal.
The table below shows how common poor and ultrarapid metabolizers are in people from different ethnic backgrounds.
| Metabolizer Status | Caucasians | African-Americans | Asians |
| 2D6 Poor Metabolizer | 5-10% | Up to 1% | 1% |
| 2D6 Ultrarapid Metabolizer | 1-5% | 2% | 0-2% |
| 2C19 Poor Metabolizer | 3-5% | 3% | 15-20% |
Inheritance
The gene variants that cause people to be poor or ultrarapid metabolizers are inherited. So, close family members may be more likely to share similar drug response profiles.
Poor Metabolizers
Poor metabolizers usually inherit variations in both copies of their drug metabolism genes that cause nonfunctional enzyme. This means that a poor metabolizer has no working copy of that particular drug metabolism gene. Usually, both parents of a poor metabolizer have at least one gene that doesn’t work. All children of a poor metabolizer will also inherit at least one gene that doesn’t work. Having one gene that doesn’t work is sometimes called an “intermediate metabolizer”.
Ultrarapid Metabolizers
The ultrarapid metabolizers that genetic testing finds have more than two copies of a drug metabolism gene. Most people just have two copies of each gene. If you have extra gene copies, you will likely make more enzyme than usual. More enzyme leads to faster metabolism of drugs broken down by that enzyme. At least one parent of an ultrarapid metabolizer should also be an ultrarapid metabolizer. Each child of an ultrarapid metabolizer has a 50% chance of also being an ultrarapid metabolizer.
