Enzyme levels may help us predict the effectiveness of drugs that act in the brain
Predicting the effectiveness of a specific drug for a specific patient can be difficult. Not only will different patients respond to the same drug differently, but an individual patient may also respond differently to the same drug at different times.
By improving our understanding of the factors that influence how a patient responds to a drug, we can better equip clinicians to prescribe patients the right drug at the right dose, improve patient care, and avoid time-consuming trial and error.
Dr. Rachel Tyndale and her team are studying how an enzyme called CYP2D6 influences the effectiveness of drugs that act in the brain. CYP2D6 metabolizes approximately 25% of clinical drugs, including many classes of drugs which work in the brain. Understanding how varying levels of CYP2D6 in the brain interact with these drugs could provide insights that will allow clinicians to create better, personalized treatment plans for patients.
We spoke to Dr. Tyndale about what her team uncovered.
What is CYP2D6, and how is it related to drug response in humans?
RT: Enzymes are proteins produced by living things that enable or speed up a specific biochemical reaction.
CYP2D6 is a member of the Cytochrome P450 family of enzymes. These enzymes enable our bodies to break down a variety of drugs. CYP2D6 is responsible for breaking down many types of drugs which act in the brain (including opioids, antidepressants, and neuroleptics).
What motivated this research?
RT: If there is a large amount of CYP2D6 is someone’s body drugs will be broken down more quickly. This can decrease or increase the effectiveness of the drug, depending on how the drug functions.
The amount of CYP2D6 enzyme in the brain varies widely from person to person because of genetic differences. In addition, CYP2D6 in the brain is also increased by environmental influences such as nicotine or alcohol.
There is evidence for sex and gender differences in response to drugs, including opioids, and in the development of drug abuse in people. These differences could be explained, in part, by different amounts of CYP2D6.
In rats there are sex differences in CYP2D in the brain; the amount of CYP2D in the female rat brain varies across the estrous cycle, and this in turn alters the response of the rat to oxycodone, an opioid pain medicine. The main goal of this study was to investigate whether the amount of human CYP2D6 in the brain during the female hormonal cycle varied enough to impact the effectiveness of drugs. This study was performed on mice who were genetically altered to add the human CYP2D6 gene to their genomes, so their bodies would produce CYP2D6, and we could study its effects.
What was the most important finding of this study, in your opinion?
RT: The most important finding was that the human CYP2D6 enzyme in the brain varied across the female hormonal cycle enough to impact how the body responded to drugs, with no detectable change in drug concentrations in the blood.
How does this change treatment in the future?
RT: Human individuals respond differently to drugs for many reasons, but human response to any drug that is metabolized by CYP2D6 enzymes in the brain may vary in females during changes in estrogen, including the menstrual cycle, pregnancy, menopause, and in those taking oral contraceptives or undergoing sex hormone therapy. Knowing this may change our predictions about how effective a drug will be for a specific patient at a specific time.
Any next steps?
RT: These studies provide support to move to human clinical studies, for example monitoring the effectiveness of opioids metabolized by CYP2D6 across the female menstrual cycle. Since CYP2D6 is a genetically variable enzyme, we anticipate that those who genetically have the enzyme will vary in opioid response across the menstrual cycle, while those who lack CYP2D6 will not.
What is the major take home message for the public?
RT: Female sex hormones, both those cycling naturally in the body and those taken therapeutically, may impact the effectiveness of drugs that work in the brain. This may explain some of the variation in drug response and could be used to optimize drug dosing and timing.
Read this month's Impact paper.
Sharon Miksys, Claire McDonald, Fariba Baghai Wadji, Frank J. Gonzalez, Rachel F. Tyndale, Human CYP2D6 varies across the estrous cycle in brains of transgenic mice altering drug response, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 135, 2024, 111108, ISSN 0278-5846. https://doi.org/10.1016/j.pnpbp.2024.111108
