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Transforming growth factor beta (TGF beta), a recently discovered polypeptide, modulates growth of normal and neoplastic cells. Since little is known concerning in vivo disposition of TGF beta, we performed studies to examine the hepatic processing of biologically active 125I-TGF beta in the rat. After intravenous injection, 125I-TGF beta disappeared from the plasma with an initial t1/2 of 2.2 min; partial hepatectomy delayed the plasma disappearance of 125I-TGF beta by 80%. 60 min after intrafemoral injection, 63% of the recovered label was present in liver and/or bile; by 90 min, most of the label removed by the liver (83%) had been slowly excreted into bile. Nearly all the label in bile (96%) was soluble in trichloracetic acid and not immunoprecipitable by specific antiserum. Colchicine and vinblastine inhibited cumulative biliary excretion of label by 28 and 37%, respectively; chloroquine and leupeptin each increased the amount of label in bile that was precipitable by trichloracetic acid and that coeluted with authentic 125I-TGF beta on molecular sieve chromatography. There was efficient first-pass hepatic extraction of 125I-TGF beta (36%) in the isolated perfused rat liver, which was inhibited by unlabeled TGF beta (but not by epidermal growth factor, EGF) and by lectins in a dose-dependent manner; prolonged fasting also decreased clearance (26%). After fractionation of liver by differential or isopycnic centrifugation, radiolabel codistributed with marker enzymes for lysosomes. The results indicate rapid, extensive, inhibitable, and organ-selective extraction of TGF beta by the liver. After extraction, TGF beta undergoes efficient transhepatic transport, extensive intracellular metabolism, and slow but complete biliary excretion of its metabolites. Liver fractionation studies and pharmacologic manipulations suggest that these processes are associated with organelles that include microtubules and lysosomes. The data suggest that the liver is a major target tissue or site of metabolism for biologically active TGF beta.
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
January 1974,
Drug metabolism and disposition: the biological fate of chemicals,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
January 1988,
Agents and actions. Supplements,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
November 1973,
The American journal of physiology,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
July 1992,
Hepatology (Baltimore, Md.),
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
March 1995,
Kidney international,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
February 2005,
Toxicological sciences : an official journal of the Society of Toxicology,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
March 1986,
The American journal of physiology,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
January 1978,
Biochemical pharmacology,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
December 1973,
The American journal of physiology,
R J Coffey, and
L J Kost, and
R M Lyons, and
H L Moses, and
N F LaRusso
March 1998,
Renal failure,
