Partially hepatectomized rats: A model for the study of the effect of toxins on the plasma protein profiles of nascent hepatocytes

Abstract

A useful framework is proposed for unifying the synthesis of plasma proteins and their degradation by, or release from, liver cells of intact and partially hepatectomized rats, in which synthesis and release of acute-phase plasma proteins occur in synchrony with the internalization and catabolism of plasma and extracellular proteins. The catabolism of proteins and other hepato-intracellular glycoproteins during sepsis or trauma is essential to provide constituent amino acids and carbohydrates for the synthesis of acute-phase plasma proteins. Increases in the plasma levels of acute-phase response proteins in sham-operated rats reached a maximum between 1 and 2 d after mock surgery, and had returned virtually to control levels within 6 d. By contrast, acute-phase proteins in the plasma of partially hepatectomized rats were decreased by 10-20% of their initial values after 24 h. A maximum acute-phase response on d 7 after the operation was characterized by an increase of 181, 445, and 19% for alpha-1-acid glycoprotein, hepatoglobin, and hemopexin, whereas other acute-phase proteins remained below control levels, for example, by 11, 25, and 38% for albumin, transferrin, and prealbumin, respectively. This delayed response suggests that the nascent liver cells had inherited the capacity of the parent cells to respond to inflammatory signal and had synthesized acute-phase plasma proteins. Accordingly, a time frame for the application of toxin to nascent hepatocytes is suggested. An increased activity (300 +/- 50%) for both bound and free neuraminidase in remnant liver tissue 19 h post partial hepatectomy suggested that hepatic regenerating factor(s) were produced in liver tissue via the hepatic bound and/or free neuraminidase-mediated desialylation of humoral substrates. By contrast, circulating levels of lysosomal enzymes alpha-fucosidase and beta-N-acetyl-D-glucosaminidase were increased marginally after 24 h but had returned nearly to control levels after 7 d, suggesting that lysosomal acid hydrolases do not play a major role in regenerative DNA synthesis, mitosis, or in the synthesis of acute-phase plasma proteins.

Acute-Phase Response in Rat to Carbon Tetrachloride-Azathioprine Induced Cirrhosis and Partial Hepatectomy of Cirrhotic Liver

“…Furthermore, no improvement of liver histology suggestive of hepatic regenerat ion was observed as similar areas of collagen matrix separa ting liver cells w ere noted as that observed for cirrhotic animals (Figure 1b). Only a slight APR was observed in contrast to that reported for PH of healthy rats (Table 1; data extracted from Fouad et al, 1992). Note.…”

“…A multiple APR has been observed after acute myocardial infarction (Kushner et al, 1978), surgical injury (Voulgari et al, 1982), severe head injury (Ferard et al, 1981), and with the development of sepsis (Witte et al, 1982). Since the liver is the main site of biosynthesis, internalization, and catabolism of APR proteins whose concentrations undergo dramatic changes during the course of inflammation or injury (Fouad et al, 1992;Sganga et al, 1985;Koj, 1974), it is appropriate to establish the validity of employing APR changes as a monitor of hepatic function during progression and regression of these traumatic events.…”

“…Acute-phase protein -1-macroglobulin is also biosynthesized by lymphocytes and fibroblasts (Turnstall & James, 1974;Mosher & Wing, 1976). APR to tissue trauma (Kushner, 1982) is related to the insult type and its magnitude (Fouad et al, 1992;McCracken et al, 1984). In humans, alterations of plasma APR levels are an important response to starvation (Smale et al, 1982), infection (Evans et al, 1980), or surgical injury (Aronsen et al, 1972;Colley et al, 1983).…”

“…These proteins are involved in APR to an injurious stimulus (Fouad et al, 1980(Fouad et al, , 1992 and in the coagulation process (Crane & Miller, 1977). Acute-phase protein -1-macroglobulin is also biosynthesized by lymphocytes and fibroblasts (Turnstall & James, 1974;Mosher & Wing, 1976).…”

Pharmacokinetics of Tacrolimus and Mycophenolic Acid Are Altered, but Recover at Different Times During Hepatic Regeneration in Rats

“…dosing of MPA in human; Bullingham et al, 1996) and the reduction in liver mass, the whole liver intrinsic clearance for MPA must decrease to 16% of normal liver at the 24th h after initiation of hepatic regeneration. Based on the total body clearance of MPA in control rats (9.29 ml/min/kg) and the hepatic plasma flow of 25.4 ml/min/kg in rats [estimated based on the reported hepatic blood flow of 55.2 ml/min/kg and hematocrit of approximately 46% in rats (Davies and Morris, 1993)], assuming lack of significant change (Ͻ20%) in the unbound fraction of MPA, since albumin, the major MPA binding protein, is decreased by only 20% at the 24th h after PHx (Fouad et al, 1992;Bullingham et al, 1996), the total body clearance of MPA at the 24th h should have been, at most, 2.12 ml/min/kg [if, accounting for the 3 times increase of blood flow per unit liver weight (only 30% liver remaining), the total body clearance should have been at most 2.25 ml/min/kg]. However, whereas the total body clearance of MPA was significantly decreased 24 h after PHx, the magnitude of reduction was much less than what was predicted based on in vitro data.…”