Inhibition of triacylglycerol biosynthesis in the regenerating rat liver by 3,4-dihydroxybutyl-1-phosphonate.
Item
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Title
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Inhibition of triacylglycerol biosynthesis in the regenerating rat liver by 3,4-dihydroxybutyl-1-phosphonate.
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Identifier
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AAI8820904
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identifier
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8820904
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Creator
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Stein, Theodore Anthony.
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Contributor
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Adviser: Burton E. Tropp
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry
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Abstract
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Mitochondrial, microsomal and peroxisomal membranes were partially purified by differential sedimentation. sn-Glycerol 3-phosphate analogues, (RS)-3,4-dihydroxybutyl-1-phosphonate, (RS)-glyceraldehyde 3-phosphate, (RS)-3-hydroxy-4-oxobutyl-1-phosphonate, (1S,3S)-1,3,4-trihydroxybutyl-1-phosphonate, and (1R,3S)-1,3,4,-trihydroxybutyl-1-phosphonate, were competitive inhibitors of both mitochondrial and microsomal sn-glycerol 3-phosphate acyltransferase reactions. An isosteric analogue of dihydroxyacetone phosphate, 4-hydroxy-3-oxobutyl-1-phosphonate, was a competitive inhibitor of the microsomal enzyme. Phenethyl alcohol was a noncompetitive inhibitor of the microsomal enzyme.;The Ki-values of (RS)-3,4-dihydroxybutyl-1-phosphonate inhibited reactions were 3.18 and 1.76 mM with the mitochondrial and microsomal enzymes, respectively. 4-Palmitoyl-sn-3-hydroxybutyl-1-phosphonate was the primary product of the mitochondrial reaction. The monoacyl product and 3,4-dipalmitoyl-sn-butyl-1-phosphanate were products of the microsomal reaction. The apparent Km for (S)-3,4-dihydroxybutyl-1-phosphonate was 2.50 and 1.38 mM for the mitochondrial and microsomal enzymes, respectively.;Following two-thirds partial hepatectomy, the triacylglycerol content of the residual liver increased, and was associated with the increase in microsomal sn-glycerol 3-phosphate acyltransferase activity, r = 0.608. The mitochondrial acyltransferase activity was unchanged. Peroxisomal dihydroxyacetone phosphate acyltransferase activity was increased.;Intraperitoneal injections of (RS)-3,4-dihydroxybutyl-1-phosphonate during liver regeneration caused a significant decrease in hepatic triacylglycerol and the mitotic index, compared to sodium chloride and sn-glycerol 3-phosphate treatment. DNA biosynthesis increased, but the liver content of DNA, RNA, phospholipid and protein was similar to control levels.;A linear incorporation of the phosphonate occurred in mouse 3T3 fibroblasts over 5 h at a rate of 4.1 pmol/h/million cells, while in human Hep-G2 hepatoma cells that rate gradually declined from 3.2 to 1.8 pmol/h/million cells over 5 h. Whole cell preparations of liver, adipose tissue, and enterocytes incorporated the phosphonate at a linear rate of 0.78 to 0.95 pmol/h/g tissue.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
