Liver system

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

R7. Richards, J. B., Evans, P. J., and Hemming, F. W., Dolichol phosphates as acceptors of mannose from guanosine diphosphate mannose in liver systems. Biochem. J. 124, 957-959 (1971). 

Minimal systemic absorption after inhalation. Metabolized in the liver (systemic absorption). Primarily eliminated in feces. Half-life 1.5-4 hr. 

Phenanthrene is transformed to trans-9,10- (major), trans-1,2- (minor), and trans-3,4-dihydrodiol (minor) metabolites via monooxygenase-catalyzed formation of arene oxides, followed by epoxide hydrolase-catalyzed hydration in mammalian liver systems.219-221 In bacterial cultures, phenanthrene is converted to cis-3,4- (major) and cis-1,2- dihydrodiols (minor) through the action of dioxygenase enzymes and molecular oxygen.221,222 Recently, Boyd et al.10 have prepared trons-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (359) and cis-3,4-dihydroxy-1,2,3,4-tetrahydrophenanthrene (360) in optically pure forms. These compounds have made possible the determination of the configurations of the trans- and cis-3,4-dihydrodiol metabolites of phenanthrene (361 and 362) as (-)-(3R,4R) and ( + )-(3S,4R), respectively. 

This chapter will focus on three types of membrane extracorporeal devices, hemodialyzers, plasma filters for fractionating blood components, and artificial liver systems. These applications share the same physical principles of mass transfer by diffusion and convection across a microfiltration or ultrafiltration membrane (Figure 18.1). A considerable amount of research and development has been undertaken by membrane and modules manufacturers for producing more biocompatible and permeable membranes, while improving modules performance by optimizing their internal fluid mechanics and their geometry. 

Nicholson JK, Lindon JC, Holmes E. Metabonomics understanding the metabolic responses of liver systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 1999 29 1181-1189. 

The effects of the P-gp inhibitor, GF120918, on the hepatobiliary disposition (biliary excretion) of doxorubicin were determined using a perfused rat liver system (270). Biliary excretion is the rate-limiting process for doxorubicin elimination. In the presence of GF120918, the biliary excretion of doxorubicin and its major metabolite, doxorubicinol, was decreased significantly without alterations in doxorubicin perfusate concentrations or doxombicin and doxorubicinol liver concentrations. In a similar study on the hepatic elimination of other P-gp substrates, including vincristine and daunorubicin, it was reported that canalicular P-gp plays a significant role in the biliary secretion of these compounds (428,429). 

On the commercial front, an artificial liver system has reached advanced clinical trial stage. Based on pig hep-atocytes immobilized in a hollow-fiber membrane module, this system provides temporary life support until a liver from a human donor is available for transplantation (Fig. 50). Also under development is an artificial pancreas intended as a permanent replacement of the native organ (Fig. 51). 

FIGURE 50 Schematic of advanced artificial liver system undergoing clinical trials (Circe Biomedical, Inc., Lexington, MA). 

The first step in the biosynthesis of cholesterol (83) from lanosterol is the reduction of the A24,25-bond, and this involves addition of a 24-pro-S proton and overall ds-stereospecificity in the rat liver system in vitro. This result has been confirmed with rat liver in vivo139 and contrasts with the situation, previously reported and now fully described in detail,140 for the steroidal triterpenoid tigogenin biosynthesized by... 

Digitalis lanata, where the pro-4R hydrogen of MVA occupied the pro-24S position and trans-addition of hydrogen was deduced. The demethylation steps in the biosynthesis of cholesterol have received much attention. In rat liver microsomes the removal of the 14a -methyl group of 24,25-dihydrolanosterol led to the formation of a A8,14-diene (84), and neither a A8(14)-ene nor a A8,14,24-triene were obligate intermediates in cholesterol synthesis.141,142 14a-Demethylation, which was preceded by A24,25-reduction in rat liver system, involved cytochrome P450, whilst the next step in the biosynthesis of cholesterol, AI4-reduction, and the reduction of the A7- and A5,7-sterols were completely inhibited by the drug AY-9944.142,143 In yeast, A14-reduction probably involved trans-addition of a hydride ion from NADPH and a proton from the medium at the 14a- and 15/3-positions, respectively.144... 

Loss of the 4,4-Dimethyl Groups.—The formation of [ H5, " C5]-4-demethyl-cyclolaudenone (73) from [2- " C,3R,4R- H]mevalonate again shows that the first methyl group lost from C-4 is labelled by [2- " C]mevalonate. Three groups have examined this stage of biosynthesis in some detail. Aerobic incubation of a rat liver system, in the absence of NAD, gave a 4j8-methyl-4a-carboxylic acid intermediate (76). This type of intermediate was also encountered when the system was inhibited by cyclic AMP. When using... 

C,2iS- H,3R]mevalonate, Bloxham and Akhtar showed that a tritium atom was lost whereas when [3a- H,26,27- C2]lanosterol was used the tritium was retained. The latter result was also observed by Hornby and Boyd. Presumably NAD is necessary for the oxidation at C-3 to a ketone prior to decarboxylation. Similarly, Miller and Gaylor showed that 4a-methyl-5a-cholest-7-en-3) -ol was oxidized only as far as the 4a-carboxylic acid, with retention of tritium at C-3 but loss from a 4a-C H3 group. In the latter case, the recovered 4a-methyl sterol showed no sign of tritium enrichment due to isotope effects. In banana, alkylation at C-24 seems to precede loss of the 4a-methyl groups. When the rat liver system was inhibited by cholestane-3, 5a,6 -triol, sterols accumulated which retained a methyl group at C-4. Both 4,4-dimethyl- and 4 -methyl-cholest-8-en-3/I-ol Uere isolated, and were shown to be converted into cholesterol under normal conditions. 

A number of K-region arene oxides have been detected as intermediates in the metabolism of the corresponding PAHs in liver systems for example, phenanthrene, benz[a]anthracene, pyrene, benzo [a]pyrene, and dibenz(a,h)anthracene. These K-region arene-oxide metabolites were generally only detected by trapping the radiolabeled intermediate. The arene-oxide metabolite 102 obtained from a-naphthoflavone was found to be sufficiently stable with respect to isomerization and resistant to attack by epoxide hydrolase so that it could be isolated and identified spectroscopically. ... 

The so-called artificial liver system was first developed by K. N. Matsumura et at (1978). This procedure comprised haemodialysis across a suspension of vital hepatocytes. Such semi-artificial liver was first used clinically in 1987 on a patient with bile-duct carcinoma and acute liver failure (K.N. Matsumura et at). 

The substrate specificity in enzymic demethylation at C-4 of steroid precursors has been explored by assay of logical precursors with rat liver systems. 4a-Formyl-4/8-methylcholestan-3/3-ol was very effectively metabolized and was a possible direct intermediate en route from 4,4-dimethylsterols, but 4-methylchoIest-3-ene, 3 j8,4jS -epoxy-4a -methylcholestane, 3a,4a -epoxy-4jS -methylcholestane, and... 

What is the condition of the patient Is their renal (kidney) or hepatic (liver) system compromised Are they pregnant or breast-feeding Is their condition one that would dictate the form of the medication to be supplied (for example, an elderly infirm patient who cannot swallow solids may require their medication in liquid form) ... 

Early experiments by Bernheim, Felix, Sealock, and their co-workers on oxidation of tyrosine by liver breis showed an uptake of four atoms of oxygen per mole of tyrosine, with the production of one molecule each of carbon dioxide and acetoacetate, but no ammonia (60, 61, 261, 262, 789, 976). Felix and Zorn (261) found alanine to be formed and considered this to arise from a direct splitting of the tyrosine side chain. Although the experiments with man and intact animals already described made it seem very probable that p-hydroxyphenylpyruvic acid and homogentisic acid were normal intermediates in tyrosine metabolism, and although homogentisic acid was known to be readily metabolized by normal liver (e.g., 208, 695, 976) Felix and co-workers (262) considered p-hydroxyphenylpy-ruvic acid and homogentisic acid not to be intermediates in the breakdown of tyrosine by the liver system. 

The mechanism whereby farnesyl pyrophosphate (6 = 2) is converted into squalene (7) has aroused much chemical and biochemical interest. An intermediate isolated from yeast is the C30 pyrophosphate (9). Rilling et suggested the cyclopropanoid structure (9a) while the cyclic pyrophosphate diester (9b) was suggested by Popjak et The universal involvement of this intermediate is supported by the incorporation of radioactivity from the diester (9), prepared from yeast, into squalene (7) by a rat liver system. However, the suggested mechanism for the formation of the diester is difficult to reconcile with the observation that nerolidyl pyrophosphate is not incorporated. 

All of the above results refer to rat liver systems. Presumably, the same result also applies to lanosterol (73) preparedby feeding yeast with [2- C,2R- H,3R]mevalonic acid or its (2S)-isomer. However, although steroids are widely distributed in nature (see also Section 13), the first formed triterpenoid in higher plants (with the exception of certain Euphorbia sp. ) is cycloartanol (75). As expected, 2,3-oxidosqualene (71) is incoi porated and the labelling pattern is presumably the same as lanosterol (73) with [2- C,3R,5R- H]mevalonic acid. When [2- C,3R,4R- H]mevalonic acid is fed, six tritium atoms are incorporated [see (75)]. The extra tritium atom is as expected at Cyclo-... 

Isomerisation from A - to A -Double Bond.— The first stage in the transfer of the double bond round ring b is an isomerisation from A - to A -(80). Although there are contrary reports there seems little doubt that this reaction may be reversible. Cholest-7-en-3) -ol in the presence of rat liver microsomes and tritiated water is radioactive on reisolation, with most of the tritium at C-9. Similarly, cholest-8-en-3) -ol is converted into [9a- H]choIest-7-en-3/ -ol by this system. In the rat liver system the 7/3-proton is lost, and this is confirmed... 

As indicated, the oxidative demethylation of lanosterol in rat liver preparations is inhibited by CO. However, if 32-hydroxylanosterol is used as substrate, CO no longer inhibits. This indicates that in animals cytochrome P-450 catalyzes only the first oxidation and that other cytochromes are used in the subsequent steps. Apparently, the yeast and liver systems are different [5]. 

Katta Bolic was in a severe stage of negative nitrogen balance on admission, which was caused by both her malnourished state and her intra-abdominal infection complicated by sepsis. The physiologic response to her advanced catabolic status includes a degradation of muscle protein with the release of amino acids into the blood. This release is coupled with an increased uptake of amino acids for "acute phase" protein synthesis by the liver (systemic response) and other cells involved in the immune response to general and severe infection. 

In this context we might point out that both the rat hepato-cyte and mouse liver systems were bathed In media containing high substrate loads, 28 alanine and 20 ethanol for the hepatocytes and 8 alanine and 20 ethanol for the mouse liver. These high loads might Induce an enhanced differential activity of certain metabolic pathways in the two systems. 

As indicated in Fig. 1, the initial step in the pathway outlined by Langdon (19,57) was believed to be the condensation of two acetyl CoA units to yield acetoacetyl CoA. Reduction of acetoacetyl CoA then followed, and in this mammalian liver system reduced diphosphopyridine nucleotide w as the hydrogen donor for this reaction. The resulting a-hydroxy-acyl-CoA com-... 

Ohashi, K., Yokoyama, T., Yamato, M., Kuge, H., Kanehiro, H., Tsutsumi, M., Amanuma, T., Iwata, H., Yang, J., Okano, T., Nakajima, Y. Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets. Nat. Med. 13, 880-885 (2007). doi 10.1038/nml576... 

The purpose of this review is to present the current status of one such system, the glucagon-sensitive adenyl cyclase from liver plasma membranes. Information obtained from other adenyl cyclase systems will be presented only to expand the general significance of the liver system. 

Tables I and II catalog the wide variety of mRNA fractions which have been faithfully translated in the rabbit reticulocyte lysate and the preincubated S30 of Krebs II cells without the addition of homologous tissue fractions. In addition, the mRNA s for mouse and rabbit globin have been translated in the preincubated mouse (and rat) liver system (Sampson et al., 1972 Sampson and Borghetti, 1972). Rabbit globin, immunoglobulin light chain, and collagen mRNA s have been translated in the Xenopus eggs and oocytes (see Chapter 4, this volume). The most obvious interpretation of these results is that messenger-specific initiation factors do not exist in animal cells and that there is no restriction on the range of mRNA s that a tissue can translate.

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