45Calcium Uptake During the Transition from Reversible to Irreversible Liver Injury Induced by D-Galactosamine In Vivo
✍ Scribed by Clemens Schiessel; Claudia Forsthove; Dietrich Keppler
- Publisher
- John Wiley and Sons
- Year
- 1984
- Tongue
- English
- Weight
- 802 KB
- Volume
- 4
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
The hepatic uptake of 46calcium (""Ca) was studied in rats after administration of D-galactosamine (3 mmoles per kg, i.v.). In contrast to measurements of the hepatic calcium content, ""Ca uptake served as a dynamic rather than a static indicator of calcium homeostasis during the transition from reversible to irreversible liver injury which occurs between 3 and 4 hr after injection of the hepatotoxin. 46Ca uptake during a 1 hr-labeling period increased from 25 to 100% above control between 3 and 4 hr and subsequently remained at this level.
The rise in 46Ca uptake and in hepatic calcium content occurred 2 to 3 hr after the D-galactosamine-induced depletion of UTP, UDP-galactose, UDP-glucose and UDP-glucuronate. The level of UDP-glucuronate was the earliest to recover. The enhanced "'Ca uptake was associated with hepatic glycogen breakdown and with an increased SGPT activity in plasma. Inhibition of RNA polymerase I1 by a-amanitin (0.5 mg per kg, i.p.) and of dolichol-dependent protein glycosylation as well as ganglioside synthesis by tunicamycin (2 mg per kg, i.p.) were used to imitate two of the early actions of D-galactosamine and indicated that an interference with either process can lead to an enhanced uptake of 46Ca into the liver in viuo.
Uridine, at a dose replenishing uracil nucleotide pools after their depletion by D-galactosamine, prevented or reversed the rise in "'Ca uptake. The antiinflammatory steroid dexamethasone, injected prior to or simultaneously with D-galactosamine also protected against the loss of calcium homeostasis and the development of liver injury. This action of the steroid may be related to its indirect phospholipase inhibition. The results emphasize the disturbance in calcium homeostasis and provide further insight into the pathogenetic sequence provoked by D-galactosamine in which uridine protects at an early stage and dexamethasone at a later stage and with less specificity for this hepatotoxin.
The hepatitis-like liver injury induced by D-galactosamine (GalN) (1) is well defined with respect to the early metabolic changes in amino sugar and uracil nucleotide metabolism (2, 3). However, the sequence linking the early depletion of hepatic UTP and UDP-hexose pools to the subsequent necrosis of hepatocytes has not been established. The consequences of UTP deficiency include inhibition of hepatic RNA synthesis (4, 5 ) ; the changes in UDP-sugar levels are associated with an interference of the synthesis of carbohydrate-containing macromolecules including glycoproteins (6, 7), glycolipids (8) and heparan sulfate (9). Irreversible hepatocyte injury in vitro and in vivo is consistently associated with a dis-