Abstract
Many members of the superfamily of hemeproteins, known as cytochrome P450 (P450 or CYP), are currently described in the literature (over 2000 at the date of this writing) [see Nelson, 2003 (http://drnelson.utmem.edu/CytochromeP450.html)]. In mammalian tissues, the P450s play central roles in drug and xenobiotic metabolism as well as steroid hormone synthesis, fat-soluble vitamin metabolism, and the conversion of polyunsaturated fatty acids to biologically active molecules. P450s also play a major role in plants by catalyzing the synthesis of a large number of secondary metabolites. Today we appreciate the unique oxygen chemistry catalyzed by the P450 enzymes as well as the dramatic effect of protein structural changes resulting in modifications of substrate specificity. Recent scientific advances have shown the importance of genetic differences (polymorphisms) in altering the physiological response of an animal to endo- and exo-biotic chemicals. In many instances these changes can be directly attributed to small differences in the amino acid sequence of a P450. The present article describes some of the early events associated with the establishment of the biological function of P450s. The 1950s and 1960s showed the transition of P450 from an unknown spectroscopic curiosity to the major player it now occupies in maintaining cellular homeostasis. The P450s are now recognized to occupy a great variety of phylogenetically distributed isoform activities. Much has been learned about the P450s, but much more remains as poorly understood. It has been almost 50 years since this class of unique proteins were discovered and their catalytic functions characterized. The present article describes the background and early history of research leading to our present knowledge of the cytochromes P450. Hopefully we will learn lessons from this history as we venture forward down the path of future scientific discovery.
Footnotes
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↵1 Abbreviations used are: P450, cytochrome P450; TPNH, triphosphopyridine nucleotide.
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Ronald W. Estabrook was born at Albany, New York on January 3, 1926. He was educated in the public school system of Albany before entering the Navy in 1943, where he was in the Navy V-12 program at Princeton University and Officer Training School at the University of Notre Dame. He served as an officer on a subchaser and a mine sweeper in Okinawa and Japan. Upon discharge from the Navy, he continued his undergraduate education at Rensselaer Polytechnic Institute, Troy, New York, where he graduated with a B.S. (Biology) in 1950; Estabrook did his graduate training in biochemistry at the University of Rochester, Rochester, New York (1954); and postdoctoral training in biophysics with Britton Chance at the Johnson Research Foundation, University of Pennsylvania. He studied at the Molteno Institute, Cambridge University, in England, with David Kielin. In 1959 Dr. Estabrook joined the faculty of the School of Medicine of the University of Pennsylvania where he advanced to the rank of Professor of Physical Biochemistry. In 1962 he published with David Cooper and Otto Rosenthal, of the Department of Surgery of the University of Pennsylvania, seminal studies describing the enzymatic (functional) properties of the hemoprotein now known as cytochrome P450. In 1968 Estabrook moved to Dallas, Texas to serve as Virginia Lazenby O'Hara Professor of Biochemistry and Chairman of the Department of Biochemistry at the University of Texas Southwestern Medical School. In 1982 Estabrook returned to the laboratory bench where he is now applying the techniques of molecular biology to the study of the enzymatic properties of different P450s expressed in different types of cells.
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Estabrook has coauthored over 280 publications including the editing of 15 books. He was elected to the National Academy of Sciences in 1979 and awarded an honorary Doctor of Medicine from the Karolinska Institut in Stockholm, Sweden in 1981 and a Doctor of Science from the University of Rochester (1981). He has served on numerous national and international advisory committees including the Governing Board of the National Research Council of the National Academy of Sciences and the Council of the Institute of Medicine of the National Academy of Sciences.
- Received April 22, 2003.
- Accepted June 4, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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