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HOMEOSTASIS AND HETEROSTASIS HANS SELYE* Claude Bernard [1] was the first to point out clearly that the internal medium of living organisms is not merely a vehicle for carrying nourishment to cells but that "it is the fixity of the 'milieu intérieur' which is the condition of free and independent life" (vol. 1, p. 404). W. B. Cannon [2] suggested the designation "homeostasis" for "the coordinated physiological processes which maintain most of the steady states in the organism" (p. 91). When faced with stressful situations that require systemic adaptation , the organism can respond through three essentially distinct mechanisms: (1) nervous—by conscious planning of defense, innate or conditioned reflexes and autonomic "emergency reactions" (partly mediated through neurohormones); (2) immunologic and phagocytic —antibody formation, activation of the reticuloendothelial system; (3) hormonal—through the syntoxic hormones which permit tolerance of the pathogen without attacking it (e.g., glucocorticoids preventing inflammation without destroying its cause) or catatoxic substances that eliminate the aggressor (e.g., certain steroids and drugs which accelerate the biodégradation of toxicants without inducing tissue resistance to them) [3], * Institut de médecine et de chirurgie expérimentales, Université de Montréal, Montreal 101, Quebec, Canada. I am greatly indebted to the following scientists for having taken time to read the original manuscript of this paper critically: Irwin M. Arias; Julius Axelrod; Allan Conney ; Sir Francis Crick; René J. Dubos; Sir John C. Eccles; Humberto Fernández-Moran; Morris Fishbein; Claude Fortier; Dwight Ingle; Arthur Kornberg; Sir Hans Krebs; HenriMarie Laborit; Ervin Laszlo; Chauncey Leake; Hans Marquardt; Irvine H. Page; DeWitt Stetten, Jr.; Edward L. Tatum; UIf Von Euler; and Paul A. Weiss. I am also most grateful for the innumerable suggestions I have received from past and present members of our institute as well as from many other personal friends too numerous to mention by name. In some manner, all of their remarks have influenced the formulation of this final text by suggesting additions, omissions, or clarifications. However, I must accept full responsibility for all the weaknesses that still remain since I could only incorporate recommendations compatible with the succinct style in which I wanted to present this concept and—much more difficult—whenever two recommendations were incompatible, I had to select one. Perspectives in Biology and Medicine · Spring 1973 I 441 In recent years, the discovery of the important role played by hepatic microsomal enzyme induction in defense against certain toxicants led to the development of a new field of pharmacology designated "xenobiochemistry" and defined as the "biochemistry of foreign organic compounds" [4, p. v]. This science is concerned with the fate of "xenobiotics" (from the Greek "xenos" and "bios" for "stranger to life"), that is, compounds which are foreign to the metabolic network of the organism [5]. At first, the term xenobiochemistry appeared to be a particularly suitable label for the new approach, because both the toxicants and the inducers of their biodégradation were foreign to the body. (Most of the initial work was performed with barbiturates, polycyclic hydrocarbons , insecticides, etc.) Indeed, Brodie and his co-workers [6], who probably did more for the development of this field than any other group of investigators, came to the conclusion that presumably the defensive enzyme systems "are not essential to the normal economy of the body, but operate primarily against the toxic influences of foreign compounds that gain access to the body from the alimentary tract" (p. 604). The large number of investigators and the fast-growing literature dealing with problems in this field have recently prompted the founding of a special journal under the name Xenobiotics. Yet, nowadays, hardly anyone doubts that neither the substrates nor the inducers of such defensive enzymes need be foreign to the body's economy [7]. Of course, in the case of poisons completely foreign to the organism, any amount in the body is excessive and hence "foreign," whereas normal body constituents become "foreign" only if their concentration greatly exceeds physiologic levels. Thus, various hormones and hormone derivatives can protect against both exogenous and endogenous damaging substances, catatoxically by inducing enzymes capable of accelerating their biodégradation, or syntoxically by increasing tissue resistance to them [3]. Among the most important natural...