Magnus Ingelman-Sundberg

Magnus Ingelman-Sundberg

Professor, Senior
Telephone: +46852487735
Visiting address: Solnavägen 9, Biomedicum B5, 17165 Solna
Postal address: C3 Fysiologi och farmakologi, C3 FyFa Farmakogenetik, 171 77 Stockholm
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About me

  • Professor of Molecular Toxicology since 1996 and research group leader in Pharmacogenetics at the Department of Physiology and Pharmacology since 2006. Section Head.

    Previous positions at Karolinska Institutet were Research Assistant in Physiological Chemistry 1976-1977; Lecturer in Physiological Chemistry 1977-1987 (appointed 1982); and Acting Professor of Physiological Chemistry 1987-1996.

    Currently leading a research group of approximately eight members.
    Our research focuses on genetic factors that contribute to interindividual variability in drug response and adverse drug reactions. A key area of our work involves a novel 3D hepatic in vitro model, which we use to study liver function, mechanisms of drug-induced enzyme induction, hepatotoxicity, and liver diseases such as steatosis, hepatitis, and fibrosis as well as its potential to characterize specificity, toxicity and stability of different siRNA drugs. Additionally, we investigate the neurological effects—such as ataxia and depression—resulting from CYP2C19 overexpression in the fetal mouse and human brain.

    Education
    Civil Engineer, Royal Institute of Technology, Stockholm 1975
    PhD in Physiological Chemistry 1975
    Docent in Physiological Chemistry 1977
    BSc. Med (med kand), Karolinska Institutet 1978.

    Academic honours, awards and prizes
    More than 550 original papers, 38, 961 citations (62, 092 in Google Scholar), and an h-factor of 101 (ISI) or 134 (Google Scholar). Member of The Nobel Assembly at Karolinska Institutet 2008-2018. Member of Editorial Advisory Boards of e.g. Trends in Pharmacological Sciences (Editorial Board), Pharmacogenetics and Genomics, Pharmacogenomics, Drug Metabolism Reviews, Drug Metabolism and Disposition, Clinical Pharmacology & Therapeutics. 

    Ranked among the world's most cited authors in Pharmacology (2014–2016, ISI Highly Cited). Recognized as a Highly Cited Researcher by Clarivate in 2017, 2021, 2022, 2023, and 2024.

    Recipient of the ERC Advanced Grant (2017–2022) and ERC Proof of Concept (PoC) Grant (2023–2025).

    Ranked No. 13 globally in Pharmacology and Pharmacy based on citation metrics emphasizing first and last authorships (PLOS Biology, Updated Science-Wide Author Databases of Standardized Citation Indicators) Plos biology citation metrics 100000 scientists.pdf..

    Ranked No. 18 out of 21, 811 researchers worldwide in Pharmacy and Pharmaceutical Sciences based on H-index. (https://www.adscientificindex.com). 

    Main supervisor to a PhD degree for 35 postgraduate students, postdoctoral training for 33 PhDs. The research group ranked as outstanding in Karolinska Institutet's External Research Assessment (ERA) in 2010.

    Awards include The Svedberg Price, The Swedish Society for Biochemistry and Molecular Biology 1989; Honorary member of The American Society for Biochemistry and Molecular Biology 1990; The Gerhard B Zbinden Lecture Award, EUROTOX 1996; The ISSX European Scientific Achievement Award 2003; The Bengt Danielsson Prize, The Swedish Academy of Pharmaceutical Sciences 2008; The John G Warner Pfizer Lectureship in Pharmaceutical Sciences, University of Michigan, USA 2011, 2018 BCPT Nordic Prize in Basic and Clinical Pharmacology and Toxicology. The 2022 R.T. Williams Distinguished Scientific Achievement Award. Honorary doctor, Syddansk Universitet. Odense, 2022.

    Commissions of trust
    ~~Programme committee of the MD curriculum: Head of studieplanekommitten 3 years, responsible for the new KI 90 GUL study plan for the MD curriculum. Docenturnämnden 6 years, Chairman of KIRT 6 years, Chairman of the Committee for Elective Periods in the MD curriculum 6 years. Vice Chairman the Recruitment Committee 3 years, Chairman of The Recruitment Committee 6 years (ending March 2014) and pro dean (vice dean) for recruitment 2 years. Chairman of study group, The Swedish Natural Science Research Council 3 years, Member of study groups at The Swedish Natural Science Research Council, The Swedish Medical Research Council, 6 years, The Norwegian Research Council for 6 years. Member of the Nobel Assembly at Karolinska Institutet 2008-2018.

    Teaching awards: Mäster from The Student Union at Karolinska Institutet 1978; The Karolinska Institutet Pedagogical Award 2000.

    Current funding as PI

    • Hjärnfonden 2023-2026
    • ERC PoC 2023-2025
    • Vetenskapsrådet 2022-2024
    • Novartis 2024-2026

Research

  • New genetic factors have been identified that may serve as pharmacogenomic biomarkers to support the individualization of drug therapy. Current research places special emphasis on the role of rare alleles and the underlying causes of missing heritability. A novel 3D spheroid system, capable of maintaining liver function for up to five weeks, is employed to investigate the regulation of hepatic gene expression, mechanisms of drug-induced enzyme induction, hepatotoxicity, and liver diseases such as steatosis, hepatitis, and fibrosis. Particular focus is given to the discovery of novel drug targets for these conditions.

    Major scientific achievements
    1. Discovery of an important role of alcohol-inducible CYP2E1 in the induction of ALD due to the enzyme's ability to produce a large amount of
    reactive oxygen radicals and initiate lipid peroxidation in the liver.
    2. Presented the first example described of duplication and amplification of active genes in the human genome in 1993.
    3. Identification of the phenotype of ultra-rapid drug metabolism and the identification and characterization of all variants of CYP2D6 and CYP2C19
    that cause such a phenotype, as well as the identification of several genetic CYP2D6 alleles causing reduced or abolished enzyme activity. All
    these genetic variants are used as pharmacogenomic drug labels by FDA and EMA.
    4. Cloning of many new human cytochrome P450 genes, including CYP2W1, a tumour- specific enzyme that catalyses the activation of anti-cancer
    drugs.
    5. Discovery that higher CYP2C19 expression in the foetal brain leads to altered brain morphology, anxiety and depression in adulthood.
    6. Description of the role of CYP2D6 and CYP2C19 polymorphisms for the optimal use of antipsychotics and antidepressants.
    7. Identification of the significance of rare genetic variants that cause interindividual variations in drug metabolism.
    8. Development of an in vitro spheroid system to study human liver function and predict drug-induced hepatotoxicity.
    9. Development of a novel triple culture in vivo like human spheroid system for studying drug induced stress reactions and dietary induced
    steatosis and NASH and its mechanisms and treatment.

Teaching

  • Been teaching MD students since 1977 in the topics of physiological chemistry, and basic pharmacology.

Articles

All other publications

Grants

  • Southern and Eastern Norway Regional Health Authority
    1 January 2022
    Biomarkers for tolerability of clozapine and risk of treatment discontinuation in patients with therapy-resistant schizophrenia<br/><br/>NOResearch stay abroadClozapine (Leponex) is the drug with the best effect in the treatment of schizophrenia. However, the risk of serious side effects limits its use. It is desirable to identify biomarkers that reflect the tolerability of the drug so that it can be used by more patients.Schizophrenia is the most serious of all mental disorders and normally requires lifelong drug treatment. Clozapine has the best clinical effect in the treatment of schizophrenia, but is also associated with an increased risk of agranulocytosis, a very serious side effect that places restrictions on its prescription. Current knowledge indicates that the mechanism behind clozapine-induced toxicity against granulocytes is linked to immunological reactions. To trigger an immunological reaction, a ‘substrate’ is required. Our hypothesis is that one or more breakdown products (metabolites) of clozapine represent ‘substrate(s)’ for such a reaction. <br/><br/>Clozapine has a complicated metabolism. Among these metabolites are so-called nitrenium ions, which are chemically very reactive substances. They bind to all types of proteins, including proteins in granulocytes. These metabolites are difficult to analyze in blood samples, precisely because they bind (covalently) to proteins in various cells. However, the body has a type of enzymes that can deactivate/capture the metabolites 'before they have time' to bind to proteins. These metabolites are quickly converted further into so-called cysteine metabolites, which are stable substances, and can thus be analyzed in blood samples. By analyzing the concentration of cysteine metabolites of clozapine in serum samples, one can thus get a picture of how much of the reactive nitrenium ions is formed.<br/><br/>The project has established a unique analysis method for measuring the level of cysteinyl metabolites in serum samples. The method is based on advanced chromatography coupled to a high-resolution mass spectrometer, which can analyze molecules with an exact mass. In total, the method can analyze the concentration/level of three cysteine metabolites of clozapine. Over the past year, the PhD fellow in the project has analyzed complete metabolite profiles of clozapine in 582 patients and compared levels of the different metabolites in relation to the genotype of "nuclear factor 1 B (NFIB)", which we have previously discovered regulates the activity of metabolizing enzymes. The results of the study show that patients who have the NFIB variant (approximately 10% of the population) have twice as high a concentration of the metabolites N-desmethylclozapine-cysteinyl, which probably reflects that these patients form more of the toxic metabolites and therefore have an increased risk of side effects and reduced tolerability of clozapine. However, these results must be verified in studies where there is better access to clinical data that reflect tolerability. We are already working on a study that will investigate both genotypes and levels of toxic metabolites in patients who terminate clozapine treatment (the hypothesis is increased prevalence of the NFIB variant and/or levels of cysteinyl metabolites in patients who terminate treatment). It is also planned to study the extent to which combination treatment with fluvoxamine, an antidepressant drug, affects the formation of cysteinyl metabolites. The hypothesis in the latter study is that fluvoxamine reduces the formation of toxic metabolites, since combination treatment with fluvoxamine is associated with better tolerability of clozapine. <br/><br/>A manuscript describing the formation of clozapine metabolites in relation to NFIB genotype has been submitted for publication, and is currently "under review" in the journal Drug Metabolism and Disposition. This article will be published in 2025. The ambition is also to publish one or both of the other substudies described above during 2025.<br/>
  • Swedish Research Council
    1 December 2021 - 31 December 2024
  • Southern and Eastern Norway Regional Health Authority
    1 January 2020 - 31 December 2023
  • A novel regimen for treatment of colon cancer using CYP2W1 as a tumor selective target
    Novo Nordisk Foundation
    1 January 2019 - 31 December 2021
  • Swedish Research Council
    1 December 2018 - 31 December 2023
  • CYP2W1 as a prognostic marker and target for pharmacological treatment of colon and liver cancer
    Swedish Cancer Society
    1 January 2018
    Each year, approximately 4,100 people receive colon cancer in Sweden and 500 people have liver cancer. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and liver cancer cells as well as in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases is in primary colon tumor. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can imagine a similar treatment. We will investigate whether CYP2W1 mRNA and peptides from CYP2W1 and deethylated DNA fragments from CYP2W1 genes can serve as new markers for the presence of colon cancer and other human tumors. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and liver cancer and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.
  • Southern and Eastern Norway Regional Health Authority
    1 January 2018 - 31 December 2022
  • European Research Council
    1 September 2017 - 30 June 2023
  • VINNOVA
    1 March 2017 - 28 February 2019
  • CYP2W1 as a prognostic marker and target for pharmacological treatment of colon and liver cancer
    Swedish Cancer Society
    1 January 2017
    Each year, approximately 4,100 people receive colon cancer in Sweden and 500 people have liver cancer. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and liver cancer cells as well as in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases is in primary colon tumor. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can imagine a similar treatment. We will investigate whether CYP2W1 mRNA and peptides from CYP2W1 and deethylated DNA fragments from CYP2W1 genes can serve as new markers for the presence of colon cancer and other human tumors. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and liver cancer and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.
  • Swedish Research Council
    1 January 2017 - 31 December 2019
  • New methods of treating colon cancer and other cancers by using CYP2W1 as a target for drug activation
    Swedish Cancer Society
    1 January 2016
    Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.
  • Swedish Research Council
    1 January 2016 - 31 December 2019
  • Swedish Research Council
    1 January 2016 - 31 December 2016
  • New methods of treating colon cancer and other cancers by using CYP2W1 as a target for drug activation
    Swedish Cancer Society
    1 January 2015
    Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.
  • New methods of treating colon cancer and other cancers by using CYP2W1 as a target for drug activation
    Swedish Cancer Society
    1 January 2014
    Each year, approximately 4,100 people receive colon cancer in Sweden. If the cancer spreads after surgical treatment, chemotherapy is needed. We have found an enzyme (CYP2W1) that is specifically only found in colon cancer cells and in some other tumor forms but not in normal tissue. We find this enzyme in higher amounts in liver metastases. We have also developed chemical compounds which by reacting by the enzyme form reactive products that kill the tumor cells. If we treat mice that have a human colon tumor containing CYP2W1 with these compounds, the tumor cannot grow. The project aims to develop even better compounds that are substrates for CYP2W1, to investigate in which other tumor forms the enzyme exists where one can envisage a similar treatment, to use mRNA and peptides from CYP2W1 gene expression as a new marker for the presence of colon cancer and other tumors in humans. Furthermore, we want to determine the enzyme structure to produce even better cancer drugs, identify the electron donors to the enzyme needed and see how the enzyme is regulated in tumor cells to find other drugs that upregulate the expression of the enzyme in the tumors. We hope through the project to be able to identify a completely new specific biomarker for colon cancer and some other tumor forms and to be able to start clinical trials with the substances we identified for a principally new way of treating colon cancer and other cancer.
  • ERA-NET NEURON Mental Disorders RDmaria aDBS
    Swedish Research Council
    1 January 2014 - 31 December 2016
  • VINNOVA
    1 November 2013 - 31 October 2015
  • Swedish Research Council
    1 January 2011 - 31 December 2015
  • VINNOVA
    1 March 2009 - 30 October 2009
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Employments

  • Professor, Senior, Department of Physiology and Pharmacology, Karolinska Institutet, 2025-2025
  • Professor, Department of Physiology and Pharmacology, Karolinska Institutet, 2020-2024

Degrees and Education

  • Docent, Karolinska Institutet, 1977

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