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Enzyme development in human and rat fetal liver Kirby, Lawrence Thomas

Abstract

A culture system has been established whereby it is possible to study the spontaneous or induced change in enzyme levels in human and rat fetal liver segments. The system is short term, i.e. of approximately 24 hours duration, and can be established with a minimum of facilities. As gestational age increased from 10 to 21 weeks, there was approximately a 14 fold decrease in the cytosol level of tyrosine transaminase (E.C.2.6.1.5, TTA) in the fetal human liver and kidney. There was a 3 fold decrease in liver cytosol phosphoenolpyruvate carboxykinase (E .C .4.1.1.32, PEPck) between 10 and 13 weeks gestational age; this enzyme level then remained relatively constant. The ratio of liver or kidney cytosol to mitochondrial PEPck was 25 to 1 in the tenth week of gestation and decreased to 6 to 1 by the eighteenth week. Thus, with increasing gestational age the mitochondrial enzyme appeared to increase in significance. The levels of kidney and liver cytosol pyruvate kinase (E .C. 2. 7.1. 40, PK) and glucose-6-phosphate dehydrogenase (E.C.1.1.1.49, G6PD) did not significantly change from 10 to 21 weeks of gestation. Comparisons between the fetal liver enzymes TTA, PEPck, PK, and G6PD in the human, pig, and rat indicated that the levels are similar for all except PEPck; this enzyme was approximately 7 times greater in pig than in human or rat. It was possible to increase the level of the cytosol enzymes PEPck and to a lesser extent TTA in fetal human liver as it was in fetal rat liver. PEPck was increased in vitro approximately 4.5 fold and TTA by about 30%. The importance of the induction of these enzymes to fetal gluconeogenesis is stressed. PEPck was increased 33 fold in the liver from a 12.5 week human fetus which had been exposed to the glucocorticoid prednisolone in utero. The importance of this induction to the gluconeogenic process is noted; also, the importance of the possible side effects of therapeutic agents given to a mother on enzymes in the fetus is stressed. Free fatty acids (FFA) or acetyl CoA caused increased levels of PEPck in human fetal liver. Also, from work with inhibitors of FFA oxidation, viz. deoxycarnitine and citral, there was an indication that the inducing effect of N⁶,O² -dibutyryl cyclic adenosine 3’ ,5’-monophosphate (dcAMP) on fetal rat liver cytosol PEPck and TTA could be partially blocked with these agents. One mechanism of induction of the gluconeogenic process, at least in the human, appears to be as follows: [See Thesis for Diagram] FFA and/or acetyl CoA may, therefore, be involved with an increase in the level of TTA and PEPck at birth when the external glucose source for the fetus is terminated. Lastly, it was possible to release TTA from the microsomal cell fraction of human and rat fetal liver with dcAMP, acetyl CoA, and oleic acid. This released enzyme was approximately 10% of the quantity normally found in human liver cytosol and approximately 20% of that found in rat liver cytosol. The suggestion is made that a reserve of TTA is available for rapid release; this is later complemented by de novo enzyme synthesis. This process may be very important at birth when a rapid dramatic increase in the level of TTA occurs.

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