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5 (1) Fujioka T, Nara F, Tsujita Y, Fukushige J, Fukami M and Kuroda M: The mechanism of lack of hypocholesterolemic effects of pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rats. Biochim Biophys Acta 1254, 7-12 (1995) (2) Fujioka T and Tsujita Y: Effects of single adminstration of pravastatin sodium on hepatic cholesterol metabolism in rats. Eur J Pharmacol 323, (1997) (3) Fujioka T, Tsujita Y and Shimotsu H: Induction of fatty acid synthesis by pravastatin sodium, a 3 hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, in rats. Eur J Pharmacol 328, (1997) (4) Tanimoto T, Onodera K, Hosoya T, Takamatsu Y, Kinoshita T, Tago K, Kogen H, Fujioka T, Hamano K and Tsujita Y: Schizostatin, a novel squalene synthase inhibitor produced by the mushroom, Schizophyllum commune. I. Taxonomy, fermentation, isolation, physico-chemical properties and bilogical activities. J Antibiotics 49, (1996) (5) Tanimoto T, Hamano K, Onodera K, Hosoya T, Kakusaka M, Hirayama T, Shimada Y, Koga T and Tsujita Y: Biological activities of novel zaragozic acids, the potent inhibitors of squalene synthase, produced by the fungus, Mollisia sp. SANK J Antibiotcs 50, (1997) (6) Bostedor RG, Karkas JD, Arison BH, Bansal VS, Vaidya S, Germanshausen JI, Kurtz MM and Bergstrom JD: Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid or with farnesol. J Biol Chem 272, (1997) (7) Fujioka T, Yao K, Hamano K, Hosoya T, Kagasaki T, Furukawa Y, Haruyama H, Sato S, Koga T and Tsujita Y: Epi-cochlioquione A, a novel acyl-coa:cholesterol acyltransferase inhibitor produced by Stachibotrys bisbyi. J Antibiotics 49, (1996)

6 Abstract-Inhibitory action of natural compounds of microbial origin on cholesterol metabolism, Tomoyuki Fujioka, Pharmacology & Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo Folia Pharmacol. Jpn. 110, Suppl 1, 75P-80P (1997)1 )Repeated administration of pravastatin significantly increased serum and liver cholesterol in rats. Hepatic LDL receptor activity was not changed and VLDL cholesterol secretion from the liver was increased. Net cholesterol synthesis in rat liver was increased after 7 days of repeated pravastatin administration. These results suggest that for rats, unlike other animals for which serum cholesterol is decreased, induced HMG-CoA reductase activity due to pravastatin treatment might overcome the inhibitory capability of pravastatin. 2) In the course of screening for squalene synthase inhibitors, novel zaragozic acids -F10863A, B, C and D-containing zaragozic acid D3 were isolated. F10863A was most potent and selectively inhibited cholesterol synthesis in freshly isolated rat hepatocytes among several cultured and isolated cells. It also showed <I>in vivo</i> serum cholestrerol-lowering effects in hamsters and marmosets. However, the inhibition for squalene synthase proved to cause acidosis due to the accumulation of farnesol-derived dicarboxylic acids in urines. 3) A novel acyl-coa: cholesterol acyltransferase (ACAT) inhibitor, designated epi-cochlioquinone A, a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent, was isolated from the fermentation broth of <I>Stachybotrys</I>bisbyi. It inhibited <I>in vivo</i> cholesterol absorption in rats by 50% at 75 mg/kg. Key words: cholesterol metabolism, HMG-CoA reductase, squalene synthase, ACAT, fermentation broth

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