Herbert Remmer

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Herbert Remmer 1965

Herbert Remmer (born March 6, 1919 in Berlin ; † June 23, 2003 in Freiburg im Breisgau ) was a German doctor, pharmacologist and toxicologist . He became particularly well known as one of the discoverers of enzyme induction through pharmaceuticals and as an advocate for a healthier world, legitimized by his science.

Life

Remmer was the only child of the owner of a delicatessen shop on Berlin's Gendarmenmarkt . After attending the Canisius College in Berlin, supported by the Jesuit order, and passing his Abitur examination in 1937, he studied economics for one semester and then medicine at the Friedrich-Wilhelms-Universität Berlin . In 1944 he passed the medical state examination, and a year later he became a at the Berlin Institute of Pharmacology at Wolfgang Heubner -built dissertation The conversion of hemoglobin to nitrites Dr. med. PhD. Appointed to the medical service, he served the medical assistant time in the field hospital of the Sankt-Gertrauden-Hospital in Berlin-Wilmersdorf . In November 1945, through the mediation of Heubner's colleague Hans Herken, he got an assistant position at the Pharmacological Institute, which had moved from the war-torn building on Dorotheenstrasse to Garystrasse in Berlin-Dahlem . After the establishment of the Free University of Berlin , the Dahlem Institute became its Pharmacological Institute, which Heubner headed until his retirement in 1953; Herken became Heubner's successor. With Herken, Remmer researched, as the distress of the time suggested, the development and treatment of hunger edema , the subject of his habilitation thesis from 1950, changes in plasma proteins in the event of inadequate protein nutrition . In the same year he married Ingeborg geb. Flemming, whom he had met in the hospital as a medical student and nurse. The marriage resulted in two daughters and a son.

Herbert and Ingeborg Remmer 2000

1954 to 1955 led Remmer to study with David Shemin (1911-1991) at Columbia University in New York, who examined the biosynthesis of heme and its components, the porphyrins . Back in Berlin, he found the topic of his future: the induction of the foreign substance metabolizing cytochrome P450 enzymes by pharmaceuticals, especially drugs . The first relevant publication dates from 1957. A collaboration with the anatomist Hans-Joachim Merker from the research department for electron microscopy at Freie Universität in 1963 and a research stay with the biochemist Ronald Winfield Estabrook (* 1926) at the University of Pennsylvania in 1964 were particularly fruitful in Philadelphia . In 1964, Remmer took over the Institute for Toxicology at the Eberhard Karls University in Tübingen on Wilhelmstrasse in Tübingen as the successor to Paul Pulewka . He headed it for 22 years and made it an international center for toxicology and biochemical pharmacology. After retiring in 1986, he moved to Ebnet , an eastern part of Freiburg im Breisgau , where he lived at Steinhalde 95 until his death. He is buried in the Bergäcker cemetery in Freiburg- Littenweiler .

research

Early works

Remmer's doctoral thesis came from one of Wolfgang Heubner's main areas of research: the question of how chemicals oxidize hemoglobin to methemoglobin . The doctoral thesis dealt with the formation of methemoglobin by nitrite ions. Before Remmer, Robert Havemann and Friedrich Jung had already experimented on this subject at the Pharmacological Institute, and the publication appeared under the names of Jung and Remmer. In Dahlem, Remmer used the experience from his doctoral thesis to further develop the hemoglobin measurement, also already used by Havemann, by means of conversion into methemoglobin cyanide. The method is now the clinical standard.

Research into starvation edema and its treatment remained an episode.

Enzyme induction

Herken and his group were interested in factors that determine the strength and duration of action of a drug, such as hormones or pretreatment with the same or a different (non-hormonal) drug. Remmers first relevant publication begins: "Since the turn of the century is known that adrenal loose animals are more sensitive to effects of many drugs as normal." In fact lasted for Decapsulated rats anesthesia with barbiturate hexobarbital (Evipan ®) longer than normal, and was reversed the anesthetic is shortened by administering the adrenal cortex hormone cortisone . Remmer went further and clarified the cause: Cortisone increased - and deficiency in the hormone decreased - the ability of the liver to oxidize hexobarbital and thus break it down. This has been demonstrated both in living test animals and in homogenized liver tissue, namely the so-called microsomes .

So much for the influence of hormones. In the introduction to Remmer's first major work on the influence of (non-hormonal) pretreatment, it says: “In a completely different way (than with cortisone), a much stronger effect on the activity of the microsomes could be achieved. When testing a number of compounds that are known to induce habituation, it was found that luminal ( phenobarbital ) has an effect on enzymatic processes in the microsomes in such a way that the breakdown of various drugs is considerably accelerated. ”Thus, phenobarbital increased - like cortisone - the oxidative breakdown of hexobarbital, and mirror-inverted to increase the breakdown the duration of a hexobarbital narcosis decreased. It was groundbreaking work. Nevertheless, it was initially rejected by Naunyn-Schmiedeberg's Archives for Experimental Pathology and Pharmacology , despite the fact that, in addition to enzyme induction by phenobarbital, it reported that, contrary to all expectations , morphine did not induce enzyme induction. The rejected version is available in abbreviated form in the journal Klinische Wochenschrift .

Independently of Remmer and at about the same time, the group of Allan H. Conney (* 1930) at the University of Wisconsin – Madison , and later at the National Institutes of Health in Bethesda (Maryland) , discovered enzyme induction by pharmaceuticals, first by carcinogenic polycyclic aromatic hydrocarbons . What was special about Remmer's approach was that it demonstrated the parallel between accelerated degradation and reduced effect and thus identified a fundamental cause of the so-called habituation to pharmaceuticals or the development of tolerance in pharmacological terminology .

In quick succession it became apparent

  • that, as after treatment with cortisone, the increase in oxidative activity was also detectable in the liver microsomes;
  • that not only phenobarbital but also numerous other pharmaceuticals were enzyme inducers, such as the antidiabetic drug tolbutamide , the antituberculotic drug rifampicin and the insecticides γ-hexachlorocyclohexane and DDT ;
  • that not only the breakdown of hexobarbital but also the breakdown of numerous other pharmaceuticals was accelerated;
  • that the microsomes whose enzyme activity was increased came from the smooth endoplasmic reticulum of the liver cells;
  • that the liver's content of a certain protein of the smooth endoplasmic reticulum, namely the content of cytochrome P450 - from today's perspective the content of the enzymes of the cytochrome P450 family - was greatly increased;
  • that the excess of cytochrome P450 enzymes was due to an increase in their new synthesis (and not to a decrease in their breakdown);
  • and that not only the new synthesis of cytochrome P450 enzymes but also the new synthesis of other enzymes could be induced by drugs, such as glucuronosyltransferases .
Proliferation of smooth endoplasmic reticulum (Ser) in the liver cell of a phenobarbital -treated rat (right); left liver cell of an untreated rat

In collaboration with Hans-Joachim Merker, Remmer made the increase in the smooth endoplasmic reticulum visible with an electron microscope in 1963. "It must have been a thrilling moment when Remmer first saw under the microscope what so far he had only conceptualized from test tube measurements." With the identification of the role of the cytochrome P450 enzymes in enzyme induction, their role in the biotransformation of Pharmaceuticals were generally recognized for the first time.

Remmer benefited the clinic from his animal experiments. His group in Tübingen developed a method for measuring enzyme activities in the human liver using needle biopsies . He found, for example, that rifampicin induced cytochrome P450 enzymes in humans, as in animal experiments. In rifampicin-treated patients, the cytochrome P450 content of the liver was three times higher and the oxidation of the estrogen ethinylestradiol was seven times faster. "This explains several clinical observations of a high incidence of pregnancies in women treated with rifampicin who used contraceptice formulations." Medically significant enough: Enzyme induction reduced the effectiveness of hormonal contraception .

It is difficult to overestimate the importance of the breakdown - the biotransformation - of pharmaceuticals and thus the enzyme induction for our confrontation with our chemical environment in general and for medicinal therapy in particular.

For a healthier world

In the later years in Tübingen and Freiburg, Remmer's efforts to derive consequences from his basic research grew. This is shown by the titles of some publications that were intended for an interdisciplinary readership:

  • 1979: The induction of enzymes that break down contaminants and their significance for therapy and toxicology
  • 1980: Do liver-protective drugs exist?
  • 1981: Lung cancer from passive smoking ?
  • 1981: Is Cancer Prevention Possible?
  • 1981: Drug Interactions. The causes and the possibility of their prevention
  • 1981: The problematic mode of action of liver protection substances
  • 1982: What are the arguments against the cigarette?
  • 1982: Improving quality of life by avoiding damage to health
  • 1984: is cancer preventable?
  • 1985: Formaldehyde : suspect cancer?
  • 1985: Diethylene glycol in wine: less a toxicological than a criminal problem
  • 1985: Secondhand smoke in the workplace: harmful or not?
  • 1986: Health risks from active and passive smoking: Significance for gynecology and obstetrics
  • 1987: Passively inhaled tobacco smoke: a challenge to toxicology and preventive medicine
  • 1987: Tobacco smoke: the most dangerous pollutant in the air in our environment
  • 1991: Smokers can cope better with passive smoke than non-smokers
  • 1999: The Protection of the Smoker: A Moral Obligation of the DGPT.

His main concern was the protection of active and even more passive smokers. The active smoker inhales the mainstream smoke, the passive smoker the sidestream smoke and the mainstream smoke exhaled by the smoker. The passive smoker ingests smaller amounts of many components of the smoke, for example nicotine , than the active smoker. Nevertheless, passive smoking also increases the risk of cancer. Remmer suggested two possible reasons. First, the sidestream smoke contains high levels of carcinogenic nitrosamines . Second, he said, the passive smoker inhales only small amounts of enzyme inducers, less than the active smoker. The active smoker therefore detoxifies some of the carcinogens in tobacco smoke through enzyme induction, the passive smoker does not.

As a member of a working group on the risk of cancer through smoking at the then Ministry for Youth, Family, Women and Health , Remmer got to know the efforts of the tobacco industry to influence the internal ministerial and public discussion. “Scientists from the 'Research Council Smoking and Health' with its president, Prof. (Klaus) Thurau (* 1928), and his secretary, Prof. Adlkofer , had a particularly significant influence on this working group . The latter dominated this advisory body. ... Even the presiding ministerial official succumbed to his fate, but it was hidden from him that ... Prof. Adlkofer was employed by the Association of the German Cigarette Industry. The author ... must admit that he saw through the tactics of unsettling the members through broad discussion of secondary problems only late. It served to distract from the immense dangers to which the cigarette smoker is exposed. ”In his last publication, from which this quote is taken, Remmer warned the German Society for Experimental and Clinical Pharmacology and Toxicology that it could“ commit to the moral duty to to stand up for the protection of smokers, not to withdraw if they (want to) do their job credibly ”.

Remmer did not live to see the disclosure of the practices of the tobacco industry in 2006, which was forced by a US court ruling in 1998. In the 1980s he asked Adlkofer for support for a paper on carcinogens in tobacco smoke. Nothing came of it. In 1988 he wrote to Adlkofer: “In retrospect I am even grateful that you did not get in touch at the time…; because as a result, I have ... not burdened my conscience with research funds that I would regret accepting today. "

student

Numerous Remmer students from Tübingen were given positions of responsibility in research and the German health system . This includes

  • Erich Pfaff (* 1934, qualified as a professor in 1973), later professor at the Tübingen Toxicological Institute,
  • Hartmut Frank (* 1935, habilitation 1986), later professor for environmental chemistry and ecotoxicology at the University of Bayreuth ,
  • Helmut Greim (* 1935, qualified as a professor in 1970), later director of the Institute for Toxicology of the Society for Radiation and Environmental Research and professor for toxicology and environmental hygiene at the Technical University of Munich ,
  • Rainer Schüppel (* 1935, qualified as a professor in 1970), later professor of pharmacology at the Technical University of Braunschweig ,
  • Karl Walter Bock (* 1935, completed his habilitation in 1973), later professor in Göttingen and from 1987 successor to Remmer at the Tübingen Toxicological Institute,
  • Ursula Breyer-Pfaff (* 1937, qualified as a professor in 1972), later professor at the Tübingen Toxicological Institute,
  • Hermann Bolt (* 1943, qualified as a professor in 1974), later director of the Institute for Occupational Physiology at the University of Dortmund ,
  • Hermann Kappus (* 1944, qualified as a professor in 1978), later professor at the Charité Dermatology Clinic ,
  • Michael Schwenk (* 1945, qualified as a professor in 1984), later at the Baden-Württemberg State Health Office,
  • Herbert Krell (1947–1997, habilitation 1987), later in the Clinic for Internal Medicine at the University of Jena ,
  • Günther Schmalzing (* 1950, qualified as a professor in 1987), later head of the molecular pharmacology department at RWTH Aachen University .

Herbert Remmer the man

According to the testimony of his friends, Remmer was proud of his research, but liked to quote from Iphigenia on Tauris : “The little things easily disappear when you look forward to see how much remains.” He enthusiastically showed guests Tübingen and the surrounding area, the castle Hohentübingen , Lichtenstein Castle and Bebenhausen , and told stories. “Who could tell a joke or story as well as Herbert Remmer?” Two of his stories, both captured by his American friends, are being discussed for this article.

His religious beliefs were important to Remmer. Until his death he belonged to the Catholic Union of New Germany . What he discovered as a scientist suggested the existence of God to him. Here he criticized, close to Hans Küng , who lives in the Tübingen neighborhood , of some of the measures taken by the Roman Catholic Church .

In his address to the German Pharmacological Society on the occasion of the award of honorary membership on July 12, 1999 in Berlin, he expressed himself about his worldview. An excerpt from the address is also being discussed for this article. In it he describes how he discovered Albert Schweitzer from nearby Alsace as his spiritual role model during his time in Freiburg .

recognition

In 1972 Remmer received the Feldberg Foundation Prize , the Paul Martini Prize in 1976 , the Lucie Bolte Prize in 1982 and the Schmiedeberg Plaque in 1985 , the highest scientific award from the German Society for Experimental and Clinical Pharmacology and Toxicology. In 1999 he also became an honorary member of this society. He was an honorary doctorate from the University of Turku in Finland .

Works (selection)

  • Together with H. Herken: About the changes in serum proteins in edema diseases. In: Dtsch. Healthcare. 1, 1946, pp. 683-687.
  • with H. Herken: Contribution to the pathogenesis of protein deficiency edema. In: Clinical weekly . 24/25, 1947, pp. 469-477.
  • with K. Ibe and G. Neuhaus: Die acute Doridenvergiftung. In: Internist. 2, 1961, pp. 247-260.
  • Fighting sleep disorders . In: Negotiations of the German Society for Internal Medicine . Springer, 1965, pp. 850-865.
  • with J. Schenkman, RW Estabrook, H. Sasame, J. Gillette, S. Narasimulu, DY Cooper and O. Rosenthal: Drug interaction with hepatic microsomal cytochrome. In: Mol. Pharm. 2, 1966, pp. 187-190.
  • with Friedrich Bär , Wolfgang Bruns , Hans-Jürgen Hapke, Dietrich Henschler , Otto Rudolf Klimmer, Wolfgang Wirth and others: Memorandum of Toxicology. German Research Foundation, Harold Boldt Verlag, Boppard 1975.

Individual evidence

  1. ↑ Helmut Greim: Review of the career of Professor Dr. Herbert Remmer. In: Drug Metabolism Reviews . 36, 2004, pp. 407-415.
  2. ↑ List of publications: Publications of Prof. Dr.med., Dr.med. (hc) Herbert Remmer. In: Drug Metabolism Reviews. 36, 2004, pp. 417-435.
  3. ↑ a b R. W. Estabrook (Ed.): Herbert Remmer Prof. em. Dr. Dr.hc 6.3.1919 - 23.6.2003. In: Special issue Drug Metabolism Reviews. 36, issue 3 & 4, 2004.
  4. ↑ Hans Herken: The Berlin pharmacology in the post-war period. Springer-Verlag, Berlin 1999, ISBN 3-540-64885-2 .
  5. ↑ H. Remmer: The influence of steroid hormones on the breakdown of Evipan in the rat. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 232, 1957, pp. 268-269.
  6. ↑ F. Jung, H. Remmer: About the conversion between nitrite and hemoglobin. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 206, 1948, pp. 459-474.
  7. ^ J. Meyer Wilmes: Herbert Remmer during the early fifties, as seen by a doctoral fellow. In: Drug Metabolism Reviews. 36, 2004, pp. 443-445.
  8. ↑ H. Remmer: The accelerated breakdown of pharmaceuticals in the liver microsomes under the influence of Luminal. In: Naunyn-Schmiedeberg's archive for experimental pathology and pharmacology. 235, 1959, pp. 279-290.
  9. ^ Klaus Starke: A history of Naunyn-Schmiedeberg's Archives of Pharmacology. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 358, 1998, pp. 1-109; here page 68
  10. ↑ H. Remmer, R. Alsleben: The activation of detoxification in the life microsomes during habituation. In: Clinical weekly. 36, 1958, pp. 332-333.
  11. ↑ Allan H. Conney: Induction of drug-metabolizing enzymes: a path to the discovery of multiple cytochromes P450. In: Annual Review of Pharmacology and Toxicology 43, 2003, pp. 1-30.
  12. ↑ F. Hofmann: Effects of pharmaceuticals on the organism: General pharmacodynamics. In: K. Aktories, U. Förstermann, F. Hofmann, K. Starke: General and special pharmacology and toxicology. 10th edition. Elsevier, Munich 2009, ISBN 978-3-437-42522-6 , pp. 5–24, here page 14.
  13. ↑ H. Remmer: Induction of drug metabolizing enzyme system in the liver. In: European Journal of Clinical Pharmacology 5, 1972, pp. 116-136.
  14. ↑ a b H. Remmer, H.-J. Flag: Enzyme induction and increase in endoplasmic reticulum in the liver cell during treatment with phenobarbital (Luminal). In: Clinical weekly. 31, 1963, pp. 276-283.
  15. ↑ a b Klaus Starke: There can be the trace of our earth floors - on pharmacologists and pharmacology. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 380, 2009, pp. 465-471.
  16. ↑ H. Remmer, HJ Merker: Effect of drugs on the formation of smooth endoplasmic reticulum and drug-metabolizing enzymes. In: Annals of the New York Academy of Sciences. 123, 1965, pp. 79-97.
  17. ↑ Ronald W. Estabrook: A passion for P450s (remembrances of the early history of research on cytochrome P450). In: Drug Metabolism and Disposition . 31, 2003, pp. 1461-1473.
  18. ↑ B. Schoene, RA Fleischmann, H. Remmer, HF von Oldershausen: Determination of drug metabolizing enzymes in needle biopsies of human liver. In: European Journal of Clinical Pharmacology. 4, 1972, pp. 65-73.
  19. ↑ H. Remmer: Drug metabolism in the human liver measured with in vitro and in vivo methods. In: drug research . 26, 1976, pp. 1262-1263.
  20. ↑ M. Eichelbaum, M. Schwab: Effects of the organism on pharmaceuticals: General pharmacokinetics. In: K. Aktories, U. Förstermann, F. Hofmann, K. Starke: General and special pharmacology and toxicology. 10th edition. Elsevier, Munich 2009, ISBN 978-3-437-42522-6 , pp. 37-64.
  21. ↑ H. Remmer: Tobacco smoke: the most dangerous pollutant in the air in our environment for humans. In: German Medical Weekly . 1212, 1987, pp. 1054-1059.
  22. ↑ H. Remmer: The protection of the smoker: A moral obligation of the DGPT . In: DGPT Forum. Issue 24, 1999, pp. 19-23.
  23. ^ Thilo Grüning, Anna B. Gilmore, Martin McKee : Tobacco industry influence on science and scientists in Germany. In: American Journal of Public Health . 96, 2006, pp. 20-32. PMC 1470431 (free full text)
  24. ↑ In the stranglehold of industry. In: Der Spiegel. 49/2005.
  25. ↑ Legacy Tobacco Documents Library (LTDL): Letter to F. Adlkofer dated January 20, 1988
  26. ↑ Fred Deckert: Remembering the good times: Herbert Remmer. In: Drug Metabolism Reviews. 36, 2004, pp. 453-458.
personal data
SURNAME Remmer, Herbert
BRIEF DESCRIPTION German doctor, pharmacologist and toxicologist
DATE OF BIRTH March 6, 1919
PLACE OF BIRTH Berlin
DATE OF DEATH June 23, 2003
Place of death Freiburg in Breisgau