Tamura O.,Showa Pharmaceutical University
Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry | Year: 2010
(5R) - [and (5S)]-5, 6-Dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides were designed and synthesized as chiral (E)-geometry-fixed a-alkoxycarbonylnitrones that exist as equilibrating mixture of (E)- and (Z)-isomers. The cyclic nitrone reacted with olefins under mild conditions to afford the main cycloadducts via the least sterically demanding exo modes. The nitrone also reacted with an allyl alcohol in the presence of magnesium bromide from the less hindered face via exo-mode to afford exclusively cycloadduct as a single stereoisomer. These reactions were applied to the syntheses of carbocyclic polyoxin C, anti-β-substituted aspartic acid, clavalanine, monatin, lycoperdic acid, neodysiherbaine A, and maremycins A and D1.
Niwa T.,Shujitsu University |
Murayama N.,Showa Pharmaceutical University |
Imagawa Y.,Shujitsu University |
Yamazaki H.,Showa Pharmaceutical University
Drug Metabolism Reviews | Year: 2015
This article reviews in vitro metabolic activities [including Michaelis constants (Km), maximal velocities (Vmax) and Vmax/Km] and drug-steroid interactions [such as induction and cooperativity (activation)] of cytochromes P450 (P450 or CYP) in human tissues, including liver and adrenal gland, for 14 kinds of endogenous steroid compounds, including allopregnanolone, cholesterol, cortisol, cortisone, dehydroepiandrosterone, estradiol, estrone, pregnenolone, progesterone, testosterone and bile acids (cholic acid). First, we considered the drug-metabolizing P450s. 6β-Hydroxylation of many steroids, including cortisol, cortisone, progesterone and testosterone, was catalyzed primarily by CYP3A4. CYP1A2 and CYP3A4, respectively, are likely the major hepatic enzymes responsible for 2-/4-hydroxylation and 16α-hydroxylation of estradiol and estrone, steroids that can contribute to breast cancer risk. In contrast, CYP1A1 and CYP1B1 predominantly metabolized estrone and estradiol to 2- and 4-catechol estrogens, which are endogenous ultimate carcinogens if formed in the breast. Some metabolic activities of CYP3A4, including dehydroepiandrosterone 7β-/16α-hydroxylation, estrone 2-hydroxylation and testosterone 6β-hydroxylation, were higher than those for polymorphically expressed CYP3A5. Next, we considered typical steroidogenic P450s. CYP17A1, CYP19A1 and CYP27A1 catalyzed steroid synthesis, including hydroxylation at 17α, 19 and 27 positions, respectively. However, it was difficult to predict which hepatic drug-metabolizing P450 or steroidogenic P450 will be mainly responsible for metabolizing each steroid hormone in vivo based on these results. Further research is required on the metabolism of steroid hormones by various P450s and on prediction of their relative contributions to in vivo metabolism. The findings collected here provide fundamental and useful information on the metabolism of steroid compounds. © 2015 Informa Healthcare USA, Inc.
Ogra Y.,Showa Pharmaceutical University
Nihon eiseigaku zasshi. Japanese journal of hygiene | Year: 2014
Copper (Cu) is an essential metal for living organisms that utilize oxygen for respiration and is required as a cofactor of redox-regulating enzymes, such as superoxide dismutase, ceruloplasmin, lysyl oxidase, tyrosinase, and dopamine β-hydroxylase. However, the redox-active property of this metal may have toxic effects on cells due to the generation of harmful reactive oxygen species. Given these circumstances, it is said that cells have a dependable system for Cu homeostasis that efficiently distributes this essential metal to cuproenzymes, thereby preventing damage to proteins, nucleic acids, sugars, and lipids. In particular, influx, efflux, and intracellular distribution with maintenance of the oxidation state of Cu are strictly regulated. Several groups of Cu-regulating factors have been identified in mammalian cells, i.e., Cu transporters, Cu chaperones, Cu-binding proteins/peptides, and others. In this review, the features of the Cu-regulating factors are concisely examined in terms of molecular mechanisms underlying Cu homeostasis in cells.
Itoh S.,Showa Pharmaceutical University |
Itoh F.,Tokyo University of Pharmacy and Life Science
Journal of Biochemistry | Year: 2012
Transforming growth factor (TGF)-β is a pleiotropic secretory protein which inhibits and potentiates tumour progression during early and late stage of tumourigenicity, respectively. However, it still remains veiled how TGF-β signalling reveals its two faces. Hoshino et al. (Autocrine TGF-β protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim, J. Biochem. 2011;149:55-65) demonstrated a new aspect of TGF-β as a survival factor in highly metastatic breast cancer cells from which TGF-β1 and TGF-β3 are abundantly expressed. They found that TGF-β suppressed the expression of BH3-only protein Bim which promotes programmed death signalling via release of cytochrome c from mitochondria. Further interestingly, forkhead box C1 (Foxc1) whose expression is suppressed upon TGF-β stimulation is involved in the expression of Bim. Based on their results, autocrine TGF-β signalling in certain breast cancers promotes cell survival via inhibition of apoptotic signalling. Thus, the inhibitors for activin receptor-like kinase (ALK)5 kinase might exert a curative influence on certain types of metastatic breast cancers. © 2012 The Authors. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
Yamazaki H.,Showa Pharmaceutical University |
Shimizu M.,Showa Pharmaceutical University
Biochemical Pharmacology | Year: 2013
Human flavin-containing monooxygenase 3 (FMO3, EC 220.127.116.11) in liver catalyzes a variety of oxygenations of nitrogen- and sulfur-containing medicines and xenobiotic substances. Loss-of-function mutations of the FMO3 gene, the enzyme responsible for trimethylamine N-oxygenation, cause the inherited disorder trimethylaminuria (also known as fish odor syndrome). In this mini-review, mutations of the FMO3 gene reported in the literature and in the National Center for Biotechnology Information single nucleotide polymorphism database were surveyed. Then, the activities of FMO3 variants in human liver microsomes and the activities of recombinantly expressed FMO3 variant proteins with respect to the oxygenation of nitrogen- and sulfur-containing drugs were summarized and the potential for drug interactions was demonstrated. Individual differences in FMO3 function were seen in subjects genotyped for homozygous FMO3 variants. Specific regions of the FMO3 C-terminus are required for functional activity. Naturally truncated FMO3 is believed to have barely detectable function, thereby explaining the relationship with severe impaired phenotypes. The present article provides fundamental, up-to-date information on the importance of human FMO3 in individual xenobiotic oxygenations, including those of new medicines and dietary-derived trimethylamine. © 2013 Elsevier Inc. All rights reserved.