AB S TRA CT Carbonate-14C was used to label the hepatic intracellular arginine pool and direct measurement of albumin synthesis was made in six rabbits before and after an 18-36 hr fast. 18 perfusion studies were performed with livers derived from fed and fasted rabbits (18-24 hr). Microsomal amino acid-incorporating ability with leucine-MH and phenylalanine-14C was compared in 17 studies, using microsomes isolated from livers taken from fed and fasted rabbits and from isolated perfused livers whose donors were fed and fasted.Albumin synthesis is rapidly inhibited by fasting. Albumin synthesis decreased 337%o in vivo and 53%o in the perfused liver. The microsomes from perfused livers taken from fed animals did not demonstrate a significantly reduced capacity to incorporate leucine-3H or phenylalanine-'4C into protein. Microsomes derived from perfused and nonperfused livers whose donors were fasted incorporated 32-54%o less tracer than microsomes obtained from fed donor rabbits. Microsomes separated from perfused livers removed from fed and fasted rabbits responded to polyuridylic acid stimulation and phenylalanine-14C incorporation rose from 58 to 171%. An 18-36 hr fast inhibits albumin production in vivo and in the perfused liver. The microsomal
A B S T R A C T The influence of alcohol on albumin synthesis was studied in the isolated perfused rabbit liver. Carbonate-"C was used to label the intracellular arginine pool which serves as the precursor of both the carbon of urea and the guanido carbon of arginine in albumin. The control group synthesized albumin at a rate of 33 mg/100 g of wet liver weight during 2.5 hr of perfusion. When alcohol, 220 mg/100 ml, was added to the perfusate, albumin synthesis decreased to between 7 and 11 mg, less than one-third the control rate. The addition of 10 mm tryptophan to perfusates containing alcohol prevented most of the inhibitory effects and albumin synthesis increased to average 24 mg. Further, the addition of alcohol to the perfusate decreased the hepatic protein/DNA ratio from 70 to 54 and the RNA/DNA ratio from 2.3 to 1.8, changes equivalent to those seen after a 24 hr fast. The addition of tryptophan to the perfusate prevented these findings in both instances.Endoplasmic membrane-bound polysomes were examined for aggregation. Alcohol decreased the quantity of heavier aggregates. Reaggregation occurred when tryptophan was added but quantitative changes in albumin synthesis could not be related to the degree of reaggregation.
Albumin synthesis is stimulated by those amino acids which increase urea synthesis and membrane bound polysome aggregation. Ornithine, an amino acid not incorporated into protein and produced from arginine in the urea cycle, is an albumin-stimulating amino acid and is the precursor of the polyamines, and we have shown that the polyamine spermine promotes bound polysome aggregation. To test the concept that ureogenesis with its generation of ornithine might play a key role in albumin synthesis regulation via the polyamine pathway, isolated livers from fasted donors were perfused with ornithine, a-difluoromethyl ornithine (DFMO), and spermine. In control experiments, albumin synthesis was 13.4 f 0.8 mg per 100 gm liver per hr and polysome aggregation was 47%. These were increased in the presence of ornithine (26.0 f 2.6 mg and 59%); if the livers were preperfused with DFMO before the addition of ornithine, then the expected increase in albumin synthesis and polysome reaggregation did not occur (16.3 f 1.4 mg and 47%).However, if spermine was present with DFMO during the preperfusion, then the addition of ornithine had the expected effect (albumin synthesis = 26.1 f 1.2 mg and polysome aggregation = 62%). This suggests that if the ornithine to putrescine pathway is blocked, ornithine does not stimulate albumin synthesis and offers support to the concepts that (a) ornithine stimulation of albumin production is via polyamine synthesis and (b) that the urea cycle plays a more important role in protein metabolism than simply the pathway for nitrogen disposal.Previous studies from this laboratory have shown that a number of amino acids when added in 10 mM concentrations to perfusates of isolated rabbit livers resulted not only in a stimulus to albumin synthesis but also to urea synthesis (1). One of these amino acids was ornithine, an intermediate in the urea cycle and an amino acid not incorporated into protein. Ornithine is also the immediate precursor of the polyamines, putrescine, spermidine, and spermine (2). The first step in the synthetic pathway to the polyamines is the decarboxylation of ornithine, catalyzed by ornithine decarboxylase to form putrescine, and it has been postulated that the effects of ornithine in stimulating albumin synthesis might be mediated via the polyamine pathway. The polyamines which are present in most tissues have been shown to
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