Acute Oral Toxicity of Trichosetin in Mice (Mus musculus L.)
Marilen M. Parungao-Balolong1, Marilet Lian B. Caluag1, Isabella Bianca D. Catibog1,
Nelia P. Cortes-Maramba2, Isidro C. Sia2, Susie O. Sio2,
Ernesto C. Balolong3, and Eufrocinio C. Marfori4*
1Department of Biology, College of Arts and Sciences,
University of the Philippines Manila, Ermita, Manila
2Department of Pharmacology and Toxicology, College of Medicine,
University of the Philippines Manila, Ermita, Manila
3Department of Biology, School of Sciences and Engineering,
Ateneo de Manila University, Katipunan Avenue, Loyola Heights, Quezon City
4National Institute of Molecular Biology and Biotechnology (BIOTECH),
University of the Philippines Los Baños, College, Laguna
corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
This study characterizes the toxicity profile of trichosetin, a novel drug which showed pronounced activity against methicillin-resistant Staphylococcus aureus (MRSA). Different doses of this drug were orally administered to male and female ICR-strain Swiss Webster mice. Characterization of toxidromes was executed during a 14-d observation period. Gross examination of the liver, heart, spleen, kidneys, and lungs of mice was performed at the termination of the study. Trichosetin showed a dose-related increase in the magnitude of biological response observed in the toxidromes and body weights of mice. However, no dose-related changes were observed in the weight and gross morphological anatomy of the major internal organs of mice. The median effective dose (ED50) for analgesia was 325.1 + 71.7 mg kg-1. The median toxic dose (TD50) for dyspnea was 417.6 + 67.4 mg kg-1. The No Observed Adverse Effect Level (NOAEL) of trichosetin was 160 mg kg-1 under the conditions of this study. The results of this study suggest that the possible target organ system of trichosetin toxicity is the central nervous system, which exhibited the most number of toxidromes.
INTRODUCTION
Trichosetin is a tetramic acid antibiotic (Fig. 1) produced in the dual culture of Trichoderma harzianum H14 and Catharanthus roseus callus (Marfori et al. 2002a). Belonging to a class that displays a wide spectrum of biological activity, this compound was found to have a marked inhibitory activity against Gram-positive bacteria such as Staphylococcus aureus. S. aureus causes a variety of nosocomial and community-acquired infections (Chambers & DeLeo 2009; Reddy et al. 2012). It is a ubiquitous microorganism colonizing the skin and muc. . . . . . . . . .
REFERENCES
ABRAMS WB, BAGDON RE, ZBINDEN G. 2003. Techniques of animal and clinical toxicology. In: Animal and Clinical Pharmacologic Techniques in Drug Evaluation. Nodine JH, Siegler PE, eds. Chicago: Year Book Medical Pub Inc. p. 45-57.
ALAD P, COCOS A. 2008. Mutagenicity potential of trichosetin, a novel drug from the dual culture of Catharanthus roseus (L.) G. Don callus and Trichoderma harzianum H14, using Rec Assay and micronucleus test. [Undergraduate Thesis]. Manila, Philippines: University of the Philippines Manila. 95p. (Available at the UP Manila Library)
ALAD P, COCOS A, BALOLONG EC, PARUNGAO MM, MARFORI EC. 2009. Mutagenicity potential of the novel drug trichosetin using the rec assay and micronucleus test. Philipp J Sci 138(2): 119-124.
BERKOWITZ BA. 2004. Development and regulation of drugs. In: Basic and Clinical Pharmacology, 10th ed. Katzung BG, ed. New York: McGraw-Hill Companies, Inc. p. 64-74.
CHAMBERS HF, DELEO FR. 2009. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 7: 629-641.
DIWA LT, PEJI RC. 2005. Antimicrobial activity of trichosetin against local clinical methicillinresistant Staphylococcus aureus (MRSA) isolates. [Undergraduate Thesis]. Manila, Philippines: University of the Philippines Manila. 37p. (Available at the UP Manila Library)
LIU C, BAYER A, COSGROVE SE, DAUM RS, FRIDKIN SK, GORWITZ RJ, KAPLAN SL, KARCHMER AW, LEVINE DP, MURRAY BE, J RYBAK M, TALAN DA, CHAMBERS HF. 2011. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 52(3): 285-292.
LOOMBA PS, TANJEA J, MISHRA B. 2010. Methicillin and vancomycin-resistant S. aureus in hospitalized patients. J Glob Infect Dis 2: 275-283.
MARFORI EC, KAJIYAMA S, FUKUSAKI E, KOBAYASHI A. 2002a. Trichosetin, a novel tetramic acid antibiotic produced in the dual cuture of Trichoderma harzianum H14 and Cathranthus roseus callus. Z Naturforsch 57c: 465-470.
MARFORI EC, BAMBA T, KAJIYAMA S, FUKUSAKI E, KOBAYASHI A. 2002b. Biosynthetic studies of the tetramic acid antibiotic trichosetin. Tetrahedron 58: 6655-58.
MARFORI EC, KAJIYAMA S, FUKUSAKI E, KOBAYASHI A. 2003. Phytotoxicity of the tetramic acid metabolite trichosetin. Phytochemistry 62: 715-721.
[PALAS] Philippine Association for Laboratory Animal Science Code of Practice for the Care and Use of Laboratory Animals Guidelines. 1999. Administrative Order no. 40 Series of 1999.
REHM SJ. 2008. Staphylococcus aureus: the new adventures of a legendary pathogen. Cleveland Clinic J Med 75(3): 177-192.
RIVERA AM, BOUCHER HW. 2011. Current concepts in antimicrobial therapy against select gram-positive organisms: Methicillin-resistant Staphylococcus aureus, penicillin-resistant Pneumococci, and vancomycin-resistant Enterococci. Mayo Clin Proc 86: 1230-42.
TARAI B, DAS P, KUMAR D. 2013. Recurrent challenges for clinicians: emergence of methicillin-resistant Staphylococcus aureus, vancomycin resistance, and current treatment options. J Lab Physicians 5:71-78.
THATI V, SHIVANNAVAR CT, GADDAD SM. 2011. Vancomycin resistance among methicillin resistant Staphylococcus aureus isolates from intensive care units of tertiary care hospitals in Hyderabad. Indian J Med Res 134: 704-708.
