David L. Drabkin

Stimulation of protein and plasma albumin synthesis in a cell-free system from livers of nephrotic rats

Abstract An accelerated hepatic synthesis of plasma proteins in rats with nephrosis, produced by means of anti-kidney sera, has been demonstrated in the intact animal (1), the isolated, perfused liver (2), and in liver slices (3). We have now investigated the incorporation of labeled amino acids into microsomal protein by an anaerobic microsome-supernatant fluid system similar to that employed by Campbell et al (4). The microsome-supernatant fluid system from nephrotic liver has been found to be about twice as active as that from the control. The RNA content of mcirosomes from nephrotic liver was elevated; the ratio of RNA to protein was increased from 0.12 in the control to 0.20 in the nephrotic microsomes. However, the increase in activity of the nephrotic system appeared to be largely due to the 100,000 g supernatant fraction.

HEMOGLOBIN, GLUCOSE, OXYGEN AND WATER IN THE ERYTHROCYTE: A Concept of Biological Magnitudes, Based upon Molecular Dimensions

Calculations have been presented to illustrate the insight which may be gained from the development of concepts of biological magnitudes upon the basis of molecular dimensions.

THE ENVIRONMENT OF FUNCTION OF LIVER AND RED BLOOD CELLS

Some years before molecular biology became a household term I had the temerity to publish a paper with the subtitle: “A Concept of Biological Magnitudes, Based on Molecular Dimensions.”’ Since that time there has been a major revolution in biological thought, amazingly engineered by a bold frontal and essentially disruptive assault upon cells. The viable fabric has been torn apart to secure the cellular organelles. Concern has been so largely directed t o the rescued cellular contents that the cell itself, functioning in an integrated community of cells,2 seems in danger of becoming an abstracti0n.j In vitro particulate systems, despite their undeniable value as experimental tools, remain closed systems in contrast with the open system of the living cell o r tissue in a living body.4 3 It is the purpose of the present communication to redirect perspective t o the artistry of function, t o the living cell functioning in the body. I propose t o test how well o r how believably we can put the cellular fragments together again, and reconstruct a valid picture of cells in tissues, and their performance in the light of the functional capacities of the whole body. Consideration will be directed t o the erythrocyte193 and, mainly, t o the parenchymal liver cell, both because of the central position of the liver in major metabolic processess and because the research interests of our laboratory, reflected in systematic studies of the metabolism of cytochrome c4l6-*O and of hepatic protein synthesis in immunochemically induced n e p h r ~ s i s , ~ . ’ l as well as in liver regenera t i ~ n , ~ . ~ i ~ > ’ have given me some familiarity with this tissue. The calculations, inferences, and proposals that follow must be regarded as first approximations, based on the best available information as assessed by the writer, doubtless with some degree of personal bias.

Independent biosynthesis of different hemin chromoproteins cytochrome c in various tissues.

Summary The participation of glycine in the biosynthesis of cytochrome c has been demonstrated. Under our conditions, the incorporation of C14 from glycine-2-C14 was of relatively very low order in the cytochrome c of heart and very high order in liver tissue which had undergone active regeneration. The data support the conclusion that in regenerating liver cytochrome c is fabricated in situ and not derived from other tissues. A rate of “turnover” for liver cytochrome c has been provisionally deduced, which is appreciably higher than the normal rate of hemoglobin “turnover.” It is tentatively proposed that chromoprotein biosynthesis is a general property of living, aerobic cells.

KINETIC BASIS OF LIFE PROCESSES: PATHWAYS AND MECHANISM OF HEPATIC PROTEIN SYNTHESIS*

In the opening paper of a conference devoted to metatmlic diseases it may appear startling to state: “Disequilibrium is a condition of life.” In several of the problems which are to be presented, pathology is but an extension of physiology. From the viewpoint of t,he biochemist and biologist, metabolic p r o m and metabolities are expressions of a living system. Adherence to a commonly accepted or usual pattern of metabolic performance has been regarded as “normal”; departure or dislocation from this loose base of reference has been viewed as “abnormal.” Actually, little separate8 these alternatives, since each remains an expression of life. Health and disease are partners, or at the least close relatives. Living processes have altered but, little from their primordial cha?, &ctm%tics, but thought about them, especially more recently, has been mdutionized. The living body, with its constituent organs and their cellular components, in the present perspective is an open or j b w system. I have discussed the characteristics and metabolic consequences of life as an open system elsewhere.’ Somct qualifying corrolaries are: 1. Such systems are not characterized by classical thermodynamic equilibria. Indeed, they are activated or triggered by departure from equilibrium. 2. Chunge is a prime requirement. “The open system exhibits only the cma8tancy of constant change. 3. In flow systems multiple steady state levels of metabolites (as in the blood plasma) are possible, and are an expression of the relative kinetia rates of infiow and outflow. 4. Such systems are characteristically dependent, often crucially, on their external environment. This has necessitated a readjustment of perspective with regard to a number of ancillary concepts ‘associated with alwical homeostatic theory.‘ S. The environmental dependence of the open system is a consequenoe When change ceases, life ceases.”1

Inhibition of hepatic macromolecule synthesis by single doses of N-hydroxy-2-fluorenylacetamide.

Abstract A single intraperitoneal injection of N-hydroxy-2-fluorenylacetamide, at a dose of 40 mg/kg, into male rats was shown to inhibit both liver regeneration after partial hepatectomy and proteinuria by rats with experimental nephrosis. These effects were accompanied by inhibition of the incorporation of labeled precursors into hepatic RNA and DNA. No such inhibitory effects were seen in normal rats. No definitive explanation for these results can be given at present, but it is suggested that this compound may be affecting the regulatory mechanisms involved in cell division.

ANALYSIS AND INTERPRETATION OF ABSORPTION SPECTRA OF HAEMIN CHROMOPROTEINS

Publisher Summary This chapter discusses the molecular spectra of various common hemin chromoproteins, their derivatives, and related compounds such as the hemochromes. It presents a study in which a graphic-mathematical analysis has been made of the absorption spectra of hemin chromoproteins. The spectrum may be conveniently subdivided into four regions, in which individual maxima have a 500-fold difference in density. The most frequently examined region is the visible, the location of α and β bands. The spectra in the near infrared, visible, and ultraviolet regions of all the derivatives examined are fundamentally similar, and represent the summational effect, which can be expressed mathematically, of the α and β bands and bands numbers 3 to 11 of an equally spaced frequency distributed series. The chapter also discusses the special significance of α and β bands, the contributions of porphyrin and protein, and the influence of coordinating ligands.

Time sequence of macromolecule synthesis in experimental nephrosis

Abstract The incorporation of labeled precursors into serum, liver and muscle protein, liver RNA, and liver DNA was measured at several time intervals after the injection of antikidney serum. Increased labeling of plasma protein, decreased labeling of muscle protein, and increased labeling of liver RNA began within three hours, while DNA labeling showed a 15–18 hour delay before undergoing a 5-fold increase. The net increase in liver DNA and RNA, which occurred between the third and fourth day, was preceded by a 60–80 per cent increase in spermidine levels. The findings are similar in many respects to the events following partial hepatectomy.