Abstract
Beta-l-2',3'-didehydro-2',3'-dideoxy-N(4)-hydroxycytidine (l-Hyd4C) was demonstrated to be an effective and highly selective inhibitor of hepatitis B virus (HBV) replication in HepG2.2.15 cells (50% effective dose [ED(50)] = 0.03 microM; 50% cytotoxic dose [CD(50)] = 2,500 microM). In the present study, we investigated the intracellular pharmacology of tritiated l-Hyd4C in HepG2 cells. l-[(3)H]Hyd4C was shown to be phosphorylated extensively and rapidly to the 5'-mono-, 5'-di-, and 5'-triphosphate derivatives. Other metabolites deriving from a reduction or removal of the NHOH group of l-Hyd4C could not be detected, although both reactions were described as the primary catabolic pathways of the stereoisomer ss-d-N(4)-hydroxycytidine in HepG2 cells. Also, the formation of liponucleotide metabolites, such as the 5'-diphosphocholine derivative of l-Hyd4C, as described for some l-deoxycytidine analogues, seems to be unlikely. After incubation of HepG2 cells with 10 microM l-[(3)H]Hyd4C for 24 h, the 5'-triphosphate accumulated to 19.4 +/- 2.7 pmol/10(6) cells. The predominant peak belonged to 5-diphosphate, with 43.5 +/- 4.3 pmol/10(6) cells. The intracellular half-life of the 5'-triphosphate was estimated to be 29.7 h. This extende...Continue Reading
References
Oct 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·S L DoongY C Cheng
Jan 23, 1974·Biochemical and Biophysical Research Communications·E Popowska, C Janion
Feb 1, 1995·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·M J FischerL H Janssen
Jun 1, 1994·Antimicrobial Agents and Chemotherapy·M T PaffD J Nelson
Apr 26, 1996·Journal of Medicinal Chemistry·T S LinY C Cheng
Sep 1, 1996·Protein Expression and Purification·S VincenzettiA Vita
Nov 1, 1996·The Journal of Clinical Investigation·P XiaG L King
Jan 10, 1997·Biochemical Pharmacology·L T MartinJ P Sommadossi
May 1, 1997·Antimicrobial Agents and Chemotherapy·J J RahnW P Gati
Jul 14, 1998·Antimicrobial Agents and Chemotherapy·Y L ZhuY C Cheng
Nov 5, 1998·Biochemical Pharmacology·M ShafieeG Maury
Apr 25, 2000·Nucleosides, Nucleotides & Nucleic Acids·W Y GaoH Mitsuya
Apr 23, 2002·Current Medicinal Chemistry·Shu-Hui Chen
May 23, 2002·Antimicrobial Agents and Chemotherapy·B Hernandez-SantiagoJ P Sommadossi
Dec 25, 2002·Antimicrobial Agents and Chemotherapy·Lieven J StuyverRaymond F Schinazi
Apr 13, 2004·Antiviral Chemistry & Chemotherapy·Dale L BarnardRobert W Sidwell
Nov 25, 2004·Antimicrobial Agents and Chemotherapy·Brenda I Hernandez-SantiagoRaymond F Schinazi
May 24, 2006·Antiviral Research·Fabien Zoulim
Feb 21, 2007·The Medical Journal of Australia·Joseph J SasadeuszGraeme Macdonald
Apr 4, 2007·Antimicrobial Agents and Chemotherapy·E MatthesH Sirma
Oct 30, 2007·Reviews in Medical Virology·Geoffrey FérirErik De Clercq
Oct 4, 2008·The New England Journal of Medicine·Jules L Dienstag