Cytochrome P450: from drug metabolism to hippocampal development
The next article in our 'in depth' series, with key people in the field, looking at their work and what it
says about the future of applied neuroscience.
His lifelong career in biochemistry, molecular toxicology and pharmacology has led to the discovery of many of the genetic bases for interindividual variation in cytochrome P450 enzymes as central to drug metabolism, and Magnus Ingelman-Sundberg’s work is increasingly relevant today as psychiatry teeters on the brink of personalised therapy.
Professor Ingelman-Sundberg has held the position of Professor of Molecular Toxicology at the Karolinska Institutet since 1996, and he currently leads a research programme focusing on genetic and epigenetic factors of importance for interindividual differences in drug response and adverse drug reactions.
With over 420 original papers under his belt, and as a Member of The Nobel Assembly at Karolinska Institutet, he is a welcome addition to the 29th ECNP Congress programme, joining others to speak on the role of brain cytochrome P450 polymorphisms in affective disorders and their treatment. The session explores the idea that certain polymorphisms could affect brain development as well as susceptibility to certain psychiatric disorders, in particular depression.
His early career saw him migrate from the field of chemistry into physiological chemistry and medicine. Speaking to ECNP, he described why he found himself drawn into the realm of pharmacogenetics: “As a person, I am interested in the chemistry of the human body (I have even edited a book called ‘The Chemistry of the Human Body’, which is used in the MD curriculum); and I think drug action and variation in drug response is clearly a topic where you combine your knowledge of chemistry interactions of drugs with genetics which can determine a little bit how the drugs respond.”
During his PhD years he set about identifying the CYP2C12 isoform of P450 – a sex-specific enzyme – in the female rat. At that time, he explained, it was unknown how drugs were metabolised and which enzymes were involved in doing so. He continued: “Of course, this led to my interest for discovering enzymes which do participate,” he said. “I got in touch with Folke Sjöqvist, a clinical pharmacologist – we were in the same administrative committee at Karolinska. We liked to chat, and we thought we should do some work together."
“He wanted to have an explanation for the great variation in CYP2D6 [a member of the cytochrome P450 systems, also described as cytochrome P450 2D6] activity between people. We started to collaborate with his patients and our genetic knowledge to resolve the fact of genetic variation, including the first description of human gene duplication and amplification, in this case causing the ultra-rapid metabolising phenotype.”
CYP2D6 is highly variable among individuals, and among ethnic groups1; it has an influcence on the metabolism of many drugs, including those targeting the CNS. As such, its pharmacological testing has become widespread in clinical practice to assess the suitability of certain drugs for individual patients. Along with the similarly polymorphic enzymes CYP2A6, CYP2D6 and CYP2C19 (the latter being the human analogy of CYP2C12 in rat), it forms the foundation of the symposium that Professor Ingelman-Sundberg chairs at the congress.
The symposium’s four speakers comprise members of the BrainCYP consortium, one of twelve such translational consortia awarded a grant under the umbrella of ERA-NET NEURON (European Research Area Networks’ Network of European Funding for Neuroscience Research). “We came together by our interests concerning the role of P450 polymorphisms in the CNS,” explained Professor Ingelman-Sundberg. “This is a big question. There is one speaker from each lab, and we complement each other well. We have a very big paper just now resubmitted to Molecular Psychiatry in this topic.”
Asked what the recent developments have been in this area, he replied: “Particularly in the CNS, very little [in terms of] direct clinical implications has come out unfortunately. What we have found in variation in the CYP enzyme is that the pharmacokinetics do vary a lot between individuals, but that the effect of P450 polymorphism on the antipsychotic or the antidepressant treatment is in most cases not so much related to the dose. It is variable because of many other factors.
“In the CNS, I would say that we have presented differences in nicotine stimulation requirement because of differences in the capacity for the body to eliminate nicotine by CYP2A6. With respect to the CYP2D6 genetic polymorphism, it is clear that codeine (which is used for pain relief) is bad for people having more than one active CYP2D6 gene. So if you are ultrarapid for CYP2D6, you form too much morphine which causes CNS depression. There have been many incidents of death among young people taking codeine being ultrarapid.”
Going on to describe his group’s discoveries in studying CYP2C19 variation among individuals, he said: “What we found was that, if you lack functional CYP2C19, you have bigger hippocampi and are in a less depressed mode.” Transgenic mice expressing human CYP2C19 gene possess shrunken hippocampi relative to wild type mice, he added.2
“We have shown that in mice, where we over-expressed CYP2C19. Also, when comparing human populations it is clear that we see, in different large cohorts, a less depressed mode among those individuals lacking an active CYP2C19 gene and larger hippocampi. How this is translated is a little bit unknown.”
This CYP2C19 enzyme is expressed in the foetal brain, but not in the adult brain – the mechanistic steps that intercede during the long journey to adulthood are, as yet, unknown. “The expression in brain during foetal life causes the less developed hippocampus and a lack of specific neurons in the hippocampus. We think there is a link between depression and the neurons whose development are controlled by CYP2C19, but we are not clear on the mechanisms behind it.”
Professor Ingelman-Sundberg, together with fellow BrainCYP consortium members Julia Stingl, Roberto Viviani and Rachel Tyndale, will be speaking at the 29th ECNP Congress 2016 on Saturday 17 September (S.05).
1. Ingelman-Sundberg M: Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5(1):6-13.
2. Persson A, et al. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the humanCYP2C19 gene. Mol Psychiatry. 2014 Jun;19(6):733-41.