L-Tryptophan increases the activity of hepatic amino acid metabolizing enzymes, affects gluconeogenesis and displays a modulatory effect on several enzymes connected with RNA synthesis. The underlying mechanism differ in individual cases and result in both an increase of enzyme synthesis de novo and a decrease of enzyme degradation. Tryptophan displays a unique effect causing aggregation of hepatic polyribosomes connected with enhanced protein synthesis and preceded by a higher transport of poly (A) messenger RNA from the nucleus to the cytoplasm. The variety of rather specific effects mediated by tryptophan brings to mind hormonal action and the existence of specific tryptophan receptors is predicted.

Most foreign compounds, including nonnutrients in foods and vapors in air, undergo extensive metabolism before they are eliminated from the body. Included in this paper are discussions of the urinary clearance of various kinds of foreign compounds, the nonspecific enzymes that catalyze the formation of many metabolites of foreign compounds, the mechanisms by which the activities of these enzymes are altered, and the pharmacokinetics of the accumulation and elimination of the metabolites after single dose administration and during constant exposure of animals to foreign compounds. The formation of toxic reactive metabolites of foreign compounds and their role in toxic reactions are discussed.

Recent research in hormone action has been aimed at studying single effects in well-defined systems. As exemplified in several chapters of this book, it has been possible to deduce a general mechanism of action of the glucocorticoids using this approach. Most hormones, and the glucocorticoids in particular, do not act as independent agents in the intact animal. Although the best known example of how glucocorticoids interact with other hormones is the amplification of the effect of those whose action is mediated by cAMP, these steroids also augment the effects of a variety of other hormones and effectors. Such interactions are of interest in clinical medicine as well, since glucocorticoid hormones are used in combination with other drugs in a number of conditions, including the treatment of asthma, allergies, and certain kinds of shock and cancer. Neither the biochemical nor the pharmacologic basis for the effects of the glucocorticoids is known. In some cases the actions of other hormones are not observed unless the tissue has first been exposed to glucocorticoids. In these instances the glucocorticoids are said to exert a "permissive effect," since they allow a process to proceed at a maximal rate even though the steroid itself has no effect on this process. There is no doubt that such examples exist, as documented above: thus the concept of a "permissive effect" does have utility. The term fails to describe the more general role the glucocorticoids play, since in many instances the steroid also has a direct effect on the process itself, or optimizes a process in which the primary effector is not as yet known. Because of these cases, and because the historically more general usage first proposed by INGLE [1] seems to have been forgotten, use of the term "permissive effect" has been avoided in this chapter. An ultimate goal in glucocorticoid hormone research is to identify the mechanisms involved in the amplification effect these hormones exert. Now that the actions of these hormones and of the hormones they interact with are being defined, such work is within the realm of feasibility.

The basic phenomena of cell fusion and hybrid cell formation are briefly described and the potential of somatic cell hybridization in studies on the expression of differentiated cellular functions is discussed. The technique of cell hybridization has been applied to two types of cellular responses to glucocorticoids. The induction of specific proteins has been investigated in hybrids of inducible cells with uninducible cells. Most studies dealt with the liver-specific enzyme tyrosine aminotransferase, whose inducibility was extinguished in the majority of the hybrids between hepatoma and nonliver cells. However, upon chromosome segregation, inducibility reappeared in some of these hybrid cells. The current ideas about cellular control of inducibility are discussed. The other major glucocorticoid-responsive system investigated in cell hybridization studies consists of lymphoid cells which are killed when exposed to the steroid. Such sensitive cells were hybridized with several types of glucocorticoid-resistant lymphoid lines, and sensitivity was found to be dominant over resistence. Hybrids between sensitive and resistant lymphoid cells, however, showed an increase in the frequency at which resistance occurred as compared to the rate observed with the wild-type parental cells. No complementation to steroid sensitivity was found in hybrids between different types of resistant cells with defects in the glucocorticoid-specific receptor system.

For over a decade, tyrosine aminotransferase induction in tissue culture cells has been a useful model system in which to study glucocorticosteroid action. In the 1960s, the establishment in culture of rat hepatomas expressing the inducible enzyme, already known to be induced in liver in vivo, provoked a wide-ranging series of experiments. The data from these experiments have provided considerable information regarding the mechanism of action of steroids. These include the fundamental facts that the steroids act directly on the induced cell in unmetablized form, that removal of steroid results in deinduction, that induction does not require DNA synthesis or massive changes in RNA synthesis, and that cytoplasmic receptor occupancy by active steroids correlates closely with the steroids' ability to affect inductions. Studies in tissue culture cells have led to the analysis of transcriptional and posttranscriptional models attempting to explain enzyme induction. The effects on enzyme induction of nonsteroid hormones and other factors have been studied through the use of tissue culture cells. Finally, cells and clones of cell variants are being used to study enzyme induction, through biochemical analysis and cell genetic approaches, including somatic cell hybridization.

The estrogen-induced synthesis of vitellogenin in the frog Xenopus and the chicken is an attractive system for investigating the molecular events leading to the activation of a specific gene. In this review article the events occurring at the level of the protein and mRNA in the cytoplasm are discussed. The available data show that the induction of vitellogenin synthesis is due to the accumulation of the corresponding vitellogenin mRNA in the cytoplasm. This suggests that transcriptional or posttranscriptional events in the nucleus are activated by the hormone. The few experiments investigating the processes in the nuclear compartment are reviewed.

Pyran copolymer (maleic anhydride-divinyl ether) has consistently reproducible molecular weight-related biologic effects associated with toxic, immunologic antitumor, and antiviral effects. Fortunately, the antitumor action occurs with the least toxic lower molecular weight fraction. Immunoadjuvant effects with this fraction would be critical to its development. Studies of polymers should include evaluation of effects on splenomegaly, splenic esterase changes, lipolysis, reverse transcriptase, nucleases, calcium flux, cyclic nucleotides, and complement and clotting elements.

Adult rat parenchymal hepatocytes can be maintained in primary culture on floating collagen membranes of prolonged periods of time. In this system the enzyme tyrosine aminotransferase is induced by glucagon, (10(-6) to 10(-8) M) hydrocortisone (10(-5) to 10(-8) M), and cyclic adenosine 3':5'-monophosphate (cAMP) (10(-4) to 10(-5) M). Epinephrine (10(-4) M) induces the enzyme only in the presence of hydrocortisone. Addition of actinomycin D inhibited the induction of tyrosine aminotransferase by hydrocortisone and cAMP. Maintenance of the cultured hepatocytes in the presence of glucose (3g/liter) results in partial suppression of the inducing effects of glucagon and cAMP. Cyclic quanosine 3':5'-monophosphate does not mimic the effects of glucose. These results demonstrate that the phenomenon of glucose repression of enzyme induction, demonstrated in vivo in mammalian liver, is independent of changes in levels of serum hormones, which occur in vivo as a result of glucose administration. This study also demonstrates that glucose repression is not mediated by changes in intracellular levels of cAMP and cyclic quanosine 3':5'-monophosphate.

Some aspects of disordered vitamin D metabolism are reviewed. The causes and consequences of diminished blood levels of 25-OH-D3 are discussed. The role of 1,25(OH)2D3 in calcium and phosphorus homeostasis is presented and the diseases associated with alterations of this hormone are described.