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In primary rat hepatocyte cultures, growth hormone was shown to depress tyrosine aminotransferase levels induced with hydrocortisone. Both induction by glucocorticoid and repression by growth hormone could be demonstrated in cultures several days old.

The metabolism of pure cis- and trans- chlordane was studied in vitro. Microsomal preparations from the livers of male rats induced with cis- or trans-chlordane in feed for ten days were used to metabolize the pure compound corresponding to the inducer. Subsequent extraction, column fractionation and combined gas chromatography-mass spectroscopy resulted in the characterization of four compounds not previously reported from an in vitro system. In addition to the substrate, trans-chlordane extracts contained species with the following molecular weights and empirical formulae: m/e 370, c 10 H 5 Cl 7 , heptachlor; m/e 352, c 10 H 6 0C1 6, a hydroxylated chlordene; and m/e 422, c 10 H 6 0C1 8 , a hydroxylated chlordane. Dichlo rochlo rdene, oxychlordane and 1- chloro- 2 -hydroxychlordene chlorohydrin were also present, With the exception of the hydroxychlordane and heptachlor, cis - chlordane extracts contained all of the metabolites found in the trans-incubates. Additionally, a fully saturated compound m/e 372, c 10 H 7 c1 7, a dihydroheptachlor, was present. The 1, 2-trans-dihydrodiol of heptachlor found in previous in vitro incubates of cis-chlordane was not present in this extract. This information has been incorporated into a proposed route for the biotransformation of the chlordanes that offers an explanation for the observed differences in the metabolism of cis - and trans-chlordane . The pathway is based on the reductive dechlorination of the chlordanes through dihydroheptachlor to dihydrochlordene. Parallel pathways of hydroxylation, desaturation and epoxide formation arise at each of these species and at chlordane itself. The trans-isomer is predominantly desaturated or hydroxylated while the cis-isomer mainly undergoes dehaloge nation.

<p> Monomeric ribosomes and very few subunits are found in mammalian cells and because subunits are required for initiation of protein biosynthesis in both mammalian and bacterial systems, this implies that the dissociation step in the ribosome cycle does not occur spontaneously. Our attention was drawn to the possibility that the monomeric ribosomes in mammalian cells could complex with a dissociation factor. This factor would perhaps be present in the cell in limited supply and would, therefore have to recycle in the course of initiation, from a completed initiation complex to another free ribosome. An assay was set up whereby the existence of a dissociation factor in a subcellular fraction of rat liver could be determined. The perfecting of the assay system for the dissociation factor yielded much information on the ionic concentration necessary for both ribosome and subunit stability. The factor was found to be present in the fraction containing the "native" subunits. This is identical to the situation which exists in E. coli. The factor is capable of dissociating rat liver monomeric ribosomes into 60S and 40S subunits. The factor was found to act on ribosomes freed of both messenger RNA and nascent protein.</p> <p> Purification of the crude dissociation factor preparation was achieved by obtaining at 4°C the 35-65% ammonium sulphate fraction. Purification was also achieved by means of an incubation of the preparation at 40°C for 30 minutes followed by a centrifugation to remove precipitated protein.</p> <p> The DF was determined to have a molecular weight in excess of 85,000 by column chromatography.</p> / Thesis / Master of Science (MSc)

Prostaglandins, released from Kupffer cells, have been shown to mediate the increase in hepatic glycogenolysis by various stimuli such as zymosan, endotoxin, immune complexes, and anaphylotoxin C3a involving prostaglandin (PG) receptors coupled to phospholipase C via a G(0) protein. PGs also decreased glucagon-stimulated glycogenolysis in hepatocytes by a different signal chain involving PGE(2) receptors coupled to adenylate cyclase via a G(i) protein (EP(3) receptors). The source of the prostaglandins for this latter glucagon-antagonistic action is so far unknown. This study provides evidence that Kupffer cells may be one source: in Kupffer cells, maintained in primary culture for 72 hours, glucagon (0.1 to 10 nmol/ L) increased PGE(2), PGF(2 alpha), and PGD(2) synthesis rapidly and transiently. Maximal prostaglandin concentrations were reached after 5 minutes. Glucagon (1 nmol/L) elevated the cyclic adenosine monophosphate (cAMP) and inositol triphosphate (InsP(3)) levels in Kupffer cells about fivefold and twofold, respectively. The increase in glyco gen phosphorylase activity elicited by 1 nmol/L glucagon was about twice as large in monocultures of hepatocytes than in cocultures of hepatocytes and Kupffer cells with the same hepatocyte density. Treatment of cocultures with 500 mu mol/L acetylsalicylic acid (ASA) to irreversibly inhibit cyclooxygenase (PGH-synthase) 30 minutes before addition of glucagon abolished this difference. These data support the hypothesis that PGs produced by Kupffer cells in response to glucagon might participate in a feedback loop inhibiting glucagon-stimulated glycogenolysis in hepatocytes.

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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21624号 / 医博第4430号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 福田 和彦, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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