Nutritional Pharmacology: Regulation of Drug and Hormone Metabolism by Components of the Human Diet
Proteins, carbohydrates, and fats in foods can affect the manner and rapidity with which the body—principally the liver—processes and biotransforms drugs, and thus alters the drugs' effectiveness. In 1976, Attallah Kappas (1926- ) and colleagues at the Rockefeller Hospital began a series of exacting metabolic studies in humans that first defined the specific effects of diet components on drug metabolism. The research focused on a class of proteins active in the liver known as cytochromes P450. These molecules contain heme, and it was Kappas' long-term interest in metabolic pathways related to heme in the liver that led him to study the effects of controlled, calculated, diets on P450-mediated chemical biotransformations in humans. The results of these studies helped to establish a firm scientific foundation for the developing field of nutritional pharmacology.
Cytochromes P450 are widely studied today because they account in considerable part for individual variations in responses to drugs, hormones, and environmental chemicals by converting them into generally inactive waste products. Knowing that many foreign chemicals increase the activity of P450s, Kappas and coworkers postulated that the major components of foods—which, of course, are complex chemicals in their own right—might also have significant effects on P450 activity and therefore on drug and other chemical metabolism in humans. In a landmark study that was designated as a Citation Classic, they found that normal volunteers who ingested a low-carbohydrate/high-protein diet of fixed, calculated composition cleared their systems of the drugs antipyrine (an analgesic) and theophylline (a bronchodilator) much more quickly than those eating a high-carbohydrate/low-protein diet. This result and subsequent research with other drugs and chemicals including natural hormones highlighted the potential diet-drug-chemical interactions for individuals in normal circumstances and for those on unusual diets; for example, people on certain weight-loss regimens, those who are malnourished or who receive only intravenous glucose for nourishment after surgery, or patients whose diet is altered for treatment of conditions such as obesity, atherosclerosis, and diabetes. The findings of these studies also raised the intriguing possibility of future use of specific food components to regulate the metabolic disposition of selective drugs or even of natural hormones such as estrogens, thus leading to the use of such dietary substances as novel "medications."
Attallah Kappas received an AB degree from Columbia (1947), following completion of his military service; and an MD degree from the University of Chicago (1950). He undertook post-graduate training at the Memorial Sloan-Kettering Cancer Center (MSKCC) and the Peter Bent Brigham Hospital, returning to Chicago in 1957. He was recruited to The Rockefeller University in 1967. In addition to heading the Laboratory of Pharmacology, he served successively during the period 1971-1991 as Program Director; Physician-in-Chief; and Vice President. He was a strong advocate of developing close collaborative relationships with Rockefeller's neighboring institutions and held for various periods joint appointments as the Vincent Astor Chair in Clinical Sciences at MSKCC; professorships in Medicine and Pharmacology at Cornell University Medical College; and Co-Directorship of the Rockefeller-Cornell Medical College MD-PhD program. He was a recipient of Commonwealth Fund and John Simon Guggenheim Memorial Foundation Fellowships; The Burroughs Wellcome Fund Special Award in Clinical Pharmacology; and the ASPET Award for Research in Therapeutics of the American Society of Pharmacology and Experimental Therapeutics. He served as an editor of the Journal of Experimental Medicine during 1971-1981. He was appointed the first Nicholson Exchange Professor from Rockefeller to the Karolinska Institute in 1985 and in 1989 became the first recipient of the newly established NIH Award for Excellence in Clinical Research. He is presently Sherman Fairchild Professor and Physician-in-Chief, Emeritus, at The Rockefeller University.
Kappas A, Anderson KE, Conney AH, and Alvares AP. Influence of dietary protein and carbohydrate on antipyrine and theophylline metabolism in man. Clin Pharmacol Ther, 1976, 20: 643-653
Alvares AP, Anderson KE, Conney AH, and Kappas A.
Interactions between nutritional factors and drug biotransformations in
man. Proc Natl Acad Sci USA, 1976, 73: 2501-2504
Conney AH, Pantuck EJ, Hsiao K-C, Garland WA, Anderson KE, Alvares AP, and Kappas A. Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef. Clin Pharmacol Ther, 1976, 20: 633-642
Anderson KE, Conney AH, and Kappas A. Nutrition and oxidative drug metabolism in man: Relative influence of dietary lipids, carbohydrate, and protein. Clin Pharmacol Ther, 1979, 26: 493-501
Kappas A, Anderson KE, Conney AH, Pantuck EJ, Fishman J, and Bradlow HL.
Nutrition-endocrine interaction: Induction of reciprocal changes in the Δ4-5α-reduction of
testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary
macronutrients in man. Proc Natl Acad Sci USA, 1983, 80: 7646-7649
Anderson KE and Kappas A. Dietary regulation of cytochrome P450. Ann Rev Nutr,1991, 11: 141-167
Principal members of the Kappas laboratory group who participated in these research programs were: Nader G. Abraham, Alvito P. Alvares, Karl E. Anderson, David R. Bickers, Allan H. Conney, George S. Drummond, Richard A. Galbraith, Mahin D. Maines, Arlene B. Rifkind, Daniel W. Rosenberg, Mohinder K. Sardana, Shigeru Sassa and Takeo Yoshinaga.
Attallah Kappas laboratory: http://www.rockefeller.edu/labheads/kappas/kappas-lab.php
At Rockefeller Attallah Kappas established the Laboratory of Pharmacology in the Hospital in 1967. His group focused on research in heme biology, and undertook a broadly based program of biochemical and clinical studies of the enzymes involved in heme synthesis and the porphyrias related to them; on heme utilization in the form of cytochrome P450 in liver and the regulation of P450-mediated drug and hormone metabolism by components of the human diet; and on the development and clinical application of synthetic heme analogues for downregulating the catabolism of heme to the bile pigment bilirubin. In each main direction of his biochemical research Dr. Kappas conducted a major program of clinical investigation. He also established at the Rockefeller Hospital a center for the diagnosis, care, and study of the diseases of porphyrin origin and, in collaborative relationships with other institutions, undertook similar efforts for studies of newborns and children with genetic or developmental forms of severe jaundice. Principal members of his laboratory group who joined in these research programs were: Nader G. Abraham, Alvito P. Alvares, Karl E. Anderson, David R. Bickers, Allan H. Conney, George S. Drummond, Richard A. Galbraith, Mahin D. Maines, Arlene B. Rifkind, Daniel W. Rosenberg, Mohinder K. Sardana, and Shigeru Sassa.