title: Acetaminophen Induced Hepatotoxicity in Wistar Rats--A Proteomic Approach.
abstract: Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP) effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups--control, nontoxic (150 mg/kg) and toxic dose (1500 mg/kg) of APAP--were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD's PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%), immunity (14%), neurological related (12%) and transporter proteins (2%), whereas in non-toxic dose-induced rats they were oxidative stress (9%), immunity (6%), neurological (14%) and transporter proteins (9%). It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.
authors.affiliation: Grassland and Forage Division, National Institute of Animal Science, RDA, Seonghwan-Eup, Cheonan-Si, Chungnam 330801, Korea. ilavenil@korea.kr.
authors.forename: Soundharrajan
authors.initials: S
authors.lastname: Ilavenil
authors.affiliation: Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia. naldhabi@ksu.edu.sa.
authors.forename: Naif Abdullah
authors.initials: NA
authors.lastname: Al-Dhabi
authors.affiliation: Grassland and Forage Division, National Institute of Animal Science, RDA, Seonghwan-Eup, Cheonan-Si, Chungnam 330801, Korea. srigopalram82@korea.kr.
authors.forename: Srisesharam
authors.initials: S
authors.lastname: Srigopalram
authors.affiliation: Department of Medicinal Crop Research, Rural Development Administration, Eumseong, Chungbuk 369-873, Korea. kyo9128@korea.kr.
authors.forename: Young
authors.initials: Y
authors.lastname: Ock Kim
authors.affiliation: Research Department of Plant Biology and Biotechnology, Loyola College, Nungambakkam, Chennai, Tamil Nadu 600 034, India. agastianloyolacollege@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Agastian
authors.affiliation: Proteomics Division, Discovery Research, Dr. Reddy's Laboratories Ltd., Miyapur, Hyderabad-500049, India. barurajasekhar@gmail.com.
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Baru
authors.affiliation: Grassland and Forage Division, National Institute of Animal Science, RDA, Seonghwan-Eup, Cheonan-Si, Chungnam 330801, Korea. choiwh@korea.kr.
authors.forename: Ki Choon
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Department of Botany and Microbiology, Addiriyah Chair for Environmental Studies, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia. mvalanarasu@gmail.com.
authors.forename: Mariadhas
authors.initials: M
authors.lastname: Valan Arasu
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar; D012984:Software; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D023382:Toxicity Tests, Acute
chemical_list: D020543:Proteome; D000082:Acetaminophen
keywords: MALDI-TOF; acetaminophen; liver injury; plasma biochemical markers
references.citation: J Androl. 2001 Mar-Apr;22(2):302-15
references.pmid: 11229805
references.citation: J Toxicol Clin Toxicol. 2001;39(5):441-5
references.pmid: 11545233
references.citation: Dev Biol. 2002 Feb 15;242(2):236-54
references.pmid: 11820818
references.citation: Hum Reprod. 2003 May;18(5):915-24
references.pmid: 12721162
references.citation: Hum Reprod. 2004 Jun;19(6):1438-47
references.pmid: 15105389
references.citation: Toxicol Appl Pharmacol. 1992 Mar;113(1):19-29
references.pmid: 1553752
references.citation: Proteomics. 2005 Mar;5(4):1003-12
references.pmid: 15712234
references.citation: Hepatology. 2005 Jun;41(6):1313-21
references.pmid: 15915461
references.citation: Clin Sci (Lond). 2005 Nov;109(5):421-30
references.pmid: 16232126
references.citation: Anal Bioanal Chem. 2007 Feb;387(4):1259-68
references.pmid: 17186225
references.citation: JAMA. 2007 Oct 10;298(14):1682-4
references.pmid: 17925520
references.citation: Drug Metab Dispos. 1990 Sep-Oct;18(5):765-70
references.pmid: 1981734
references.citation: N Engl J Med. 1988 Dec 15;319(24):1557-62
references.pmid: 3059186
references.citation: Br Med J. 1966 Aug 27;2(5512):497-9
references.pmid: 5913083
references.citation: Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327-31
references.pmid: 6424115
references.citation: J Pharmacol Exp Ther. 1978 Jul;206(1):218-26
references.pmid: 660552
references.citation: Clin Nephrol. 1980 Oct;14(4):201-5
references.pmid: 7428194
references.citation: Mol Pharmacol. 1980 Nov;18(3):536-42
references.pmid: 7464816
references.citation: Toxicol Appl Pharmacol. 1995 Oct;134(2):313-20
references.pmid: 7570608
references.citation: Fundam Appl Toxicol. 1996 Feb;29(2):229-37
references.pmid: 8742320