Exocytotic Excretion of Dextran Sulfates From Liver to Bile

Abstract

Abstract-When dextran "S-sulfates (DSs), anticoagulants and antilipemic agents, were intravenously given to rats, the specific radioactivity was five to twenty times higher in the lysosomal than in the other subcellular fractions of liver, but the counts in this fraction were only 10% of total radioactivity distributed to the liver. Therefore, we investigated the biliary excretion of 35S-DSs with a similar sulfur content of 18% and three different average molecular weights (AMW) of 3000, 20,000, and 200,000. The excretion rate was about 2 % of the radioactivity given, per hour, after intravenous administration of35S-DS with AMW of 20,000, 10 mg/kg. At this time, acid phosphatase activity and calcium content of bile also were increased, and well correlated with the amount of the radioactivity excreted to bile. The amount of the radioactivity distributed to the lysosomal fraction is correlated with the enhanced activities of Nat-K+-dependent and Ca2+-activated ATPase in this fraction, indexes of endocytotic and exocytotic transports.DSs significantly enhanced 45Ca levels of the lysosomal, but not the cytosol fraction when 45CaCl2 was given alone or simultaneously with DSs. According to our previous reports that DSs are transferred to the lysosomal fraction of liver and intestinal mucosa by endocytosis, the present results suggest that DSs, especially with high AMW and which are distributed to liver lysosomes are rapidly excreted into bile by exocytosis and accompanied by calcium and lysosomal enzymes.Macromolecules can enter into cells (1-3). DeDuve and Wattiaux (4) reported that dextran, a high molecular weight polysaccharide, is transported to liver cells and accumulates within endocytotic granules in the cytosol. Most of the granules can be collected in the lysosomal fraction by subcellular fractionation (5). Aronson and Davidson (6) and our group (7) have indicated that acid polysaccharides, chondroitin sulfates and dextran sulfates (DSs), are found in the lysosomal fraction of rat liver after intravenous administration.When 35S-labeled DS with an average molecular weight of 200,000 was given intraduodenally, the lysosomal fraction of intestinal mucosa contained 40 % of the tissue radioactivity (8). In the liver lysosomal fraction only 10 % of the tissue radioactivity was found after intravenous administration of the DS (7).Acid polysaccharides distributed to liver lysosomes are eliminated by catabolism (6) and biliary excretion. DeDuve and Wattiaux (4) indicated that dextran which was transferred to liver lysosomes is rapidly excreted to bile. Therefore, the difference in lysosome/ tissue ratio of the radioactivity between liver and intestinal mucosa may be due to the rapid biliary excretion of 35S-DSs distributed to liver lysosomes. Thus, we examined the biliary excretion of DSs with a similar sulfur content of 18 % and three different average molecular weights of 3000, 20,000, and 200,000. Our findings are reported herein.

Comparison of Body Distribution of Poly(vinyl alcohol) with Other Water-soluble Polymers after Intravenous Administration

“…This would account for the appearance of a peak in the carcass and kidney accumulation of PVA. The decay of the large molecule in the liver may be due to biliary excretion as reported previously (Kagawa & Tomizawa 1980;Hashida et a1 1990).…”

“…Drug conjugation with water-soluble polymers enables the half-life of the drug in the blood to be prolonged and the distribution profile to be changed, but the body distribution of the drug chemically modified by polymers has been found to be greatly affected by the molecular weight (Garlick & Renkin 1970;Kagawa & Tomizawa 1980;Takakura et a1 1987b;Nagy et a1 1989;Nakagomi et a1 1989), the electric charge (Brenner et a1 1978;Takakura et a1 1987a;Barrowcliffe et a1 1990), the biological properties (Varga et a1 1977;Shen & Ryser 1979;Davis & Preston 1981;Kulkarni et a1 1981;Kobayashi et a1 1988), and the type of the carrier polymer used (Przybylski et a1 1978a, b). For the drug modification, poly(ethy1ene glycol) (PEG) has been most widely used because of its long half-life in the blood and its low interaction with organs (Abuchowski et a1 1977;Savoca et a1 1979;Cecchi et a1 1981;Hershfield et a1 1987;Katre et a1 1987;Veronese et a1 1989).…”

Triton WR-1339, A Lysosomotropic Compound, Is Excreted into Bile and Alters the Biliary Excretion of Lysosomal Enzymes and Lipids

“…We propose that these observations, taken together, provide direct evidence for a lysosome-to-bile hepatic excretory pathway by which exogenous (e.g., '3H-Triton WR-1339) and endogenous (e.g., lysosomal enzymes) material within hepatocyte lysosomes may undergo biliary excretion. Supporting this conclusion is a recent report that dextran sulfate, another lysosomotropic compound, is also ex- creted into bile parallel to acid phosphatase, a lysosomal enzyme (27). Although the physiologic importance of such a vesicular excretory route remains to be established, it could provide the hepatocyte a final common pathway for disposing of materials, such as lipoproteins (6, 7 , 28), metals (3), and drugs (29), which are sequestered in hepatocyte lysosomes for storage or degradation.…”

Reduction of low‐density lipoproteins with dextran sulfate in patients with familial hypercholesterolemia

“…Some of the untoward reactions seen in our patients, such as posttreatment leukocytosis, flushing, fatigue, headache, hives, hypotension, low back pain, and nasal congestion, appeared to be due to complement activation, since they were lessened when complement activation was reduced by elimination of Mg++ from the precipitation solution. A rise in hepatic enzymes or gastrointestinal discomfort may have been caused by DxS, since it is known to be excreted in both bile [16] and urine [17], as well as metabolized in the liver [HI. In addition to thrombocytopenia, alopecia and arthralgia have been the most prominent side effects seen by other investigators during the administration of DxS to humans 1191.…”