MIM lllii [Mil SPLEEN m n [Itii] mil
C. Particulates and Cell-Free Systems
A review of mitochondrial physiology by Lehninger (214) included discussion of studies with thyroxine. Tapley and Cooper (49) reported that this hormone uncouples oxidative phosphorylation only in intact mitochondria, not in isolated enzyme systems. This observation, and induction of mitochondrial swelling by thyroxine (214), were the basis for suggesting that the hormone might alter mitochondrial permeability at
physiological concentrations. Melhuish and Greenbaum (50) obtained similar evidence that growth hormone acts on the mitochondrial surface.
With β-hydroxybutyrate as substrate, liver mitochondria from STH-treated rats gave lower P : 0 ratios than those from controls, due, how
ever, to increase in oxygen uptake. This difference was not observed when digitonin particles from the mitochondria of control and treated groups were compared. In vitro experiments added ACTH, insulin, and growth hormone to the growing list of substances that induce mito
chondrial swelling (estimated from absorbance measurements). Growth hormone also increased the number of particles in the mitochondrial fraction of liver cells (215).
Reid followed up earlier interests (216) with studies on incorporation of C1 4-orotic acid into RNA of various subcellular fractions (217). In a study by Reid et al. (218) incorporation of C1 4-leucine into liver pro
tein was also examined. Differences between results obtained and those reported for N1 5 involve two fundamental problems: (1) relative merits of paired feeding and ad lib. feeding in control and treated rats with quite different requirements, and (2) relative merits of C1 4 and N1 5 as tracers. With respect to the latter problem, the author feels that N1 5 is more useful for studying nitrogen transfer and "metabolism of nitrogen from individual sources" than for studying incorporation of individual amino acids into protein.
Balis et al. (219) made the interesting observation that labeling of purines of ribonucleoprotein particles with C1 4-glycine occurred much more slowly than labeling of the protein component, and was not markedly affected by growth hormone. Proteins of the RNP particle were almost maximally labeled 15 minutes after intravenous injection of C1 4-glycine in rats, while labeling of adenine required 60 minutes, and that of guanine even longer. Stimulation of serine synthesis by growth hormone was also reported.
Applications of electron microscopy are too extensive to be con
sidered in detail. Cardell (220) recently discussed a group of studies concerned with ultrastructure and function of the anterior lobe.
Korner's important contributions to two symposia (221, 222) demon
strate the usefulness of cell-free, amino acid incorporating systems for investigating the mode of action of growth hormone, insulin, and other hormones. Essentially, they involved setting up such systems in which microsomes, or later ribosomes, from livers of normal, hypophysectomized, STH-treated-hypophysectomized, or adrenalectomized rats were used in various combinations with soluble fractions from these sources. Systems containing ribosomes from livers of intact rats incorporated amino acids equally well, whether the soluble fraction from intact or
tomized rats was used. Systems containing ribosomes from hypophysec-tomized, untreated rats were less active, regardless of the source of the soluble fraction. Thus the defect produced by hypophysectomy was localized in the ribosome; the amino acid activating and transfer system remained intact. The ribosomal defect was partly corrected by treating hypophysectomized rats with growth hormone, but not by adding the hormone to the system in vitro. Further studies (222a) suggest that growth hormone may regulate the amount of messenger RNA associated with microsomes.
V I I . OBSERVATIONS WITH HUMAN GROWTH HORMONE ( H G H ) IN MAN
Effects of STH and ACTH on experimental tumors have been studied extensively (223). Otherwise, growth hormone literature has contained relatively little about growth since gigantism was induced in rats. Species specificity was one reason for this. Frustrating trials of nonprimate growth hormone in man are mentioned in the excellent review by Raben
(224), which also includes his method and that of Li and Papkoff for preparing HGH, discussion of its metabolic effects in man, and initial results of treating hypopituitary dwarfs.
The chemistry of STH, and its widespread effects on metabolism, have received much attention. A glance at papers included in a collo-quium (225) and a symposium (226) suggests that this will continue to be true in the case of HGH. Knowledge of relationships between struc-ture and function of proteins and insight into metabolic problems of all types may be two of the most important results of studies with pituitary hormones. Why HGH is effective in lower orders of mammals while man responds only to HGH or simian STH (226a, 226b) is a topic of major interest, considered in a recent review (160a).
Many direct applications are being explored. A well-controlled study indicates that HGH does not prevent postoperative nitrogen loss (227).
Promising results have been reported in malnutrition (228). Quantitative studies in 15 hypopituitary dwarfs yielded plasma growth hormone values (sulfation factor) below those of 27 normal children; values were not reduced in 26 dwarfs in which there was no other evidence of pituitary deficiency, or in 11 children whose growth was retarded by nonpituitary diseases (229).
In general, metabolic effects of HGH in man recapitulate those observed in animals, even in some troublesome details. Maintaining an effect requires increasing doses; and nitrogen stored per milligram of HGH varies too much for assay purposes. Rentention of potassium, sodium, chloride, and water have all been induced with HGH (230, 231).
Calcium output usually increases, and in cases of lead poisoning, HGH mobilized lead, indicating that bone calcium was drawn upon (232). Use of HGH in an obese patient (233) was not as effective as one might anticipate, considering effects of HGH on mobilization of free fatty acid and participation of growth hormone in calorigenesis in animals.
HGH increased blood sugar, glucosuria, and ketosis in hypophysec
tomized juvenile diabetics (231). In an extensive recent study involving all possible combinations of hypophysectomy, pancreatectomy, and adrenalectomy, ketonemia in depancreatized dogs was observed only when the pituitary, or growth hormone, and the adrenals, or Cortisol, were present (234). Thus the conclusions reached by Long and Lukens (154) have been confirmed and defined in terms of specific pituitary and adrenal factors.
The fact that sheep prolactin produces nitrogen storage and other metabolic effects similar to those of HGH in hypopituitary dwarfs (235) occasioned considerable surprise, and will no doubt stimulate further chemical studies.
ACKNOWLEDGMENTS
The author takes pleasure in acknowledging his indebtedness to Dr. H. C.
Choitz and Dr. T. G. Vitti for supplying some of the references, and to Miss Dorothy Reid for assistance in preparing the manuscript.
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