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.
Highlights
The liver is the largest complex organ in the body which plays an important role in the internal environment maintenance by its multiple functions
N-Acetyl-p-benzoquinoneimine (NAPQI), is an intermediate product of acetaminophen produced in the presence of cytochrome-p450 that causes hepatic damage [2] and tubular necrosis in the kidney [3] in both humans and experimental animals [4]
A large amount of APAP is metabolized by the presence of P450s, which leads to reduced GSH levels by NAPQI conjugation and covalent binding of NAPQI
Summary
The liver is the largest complex organ in the body which plays an important role in the internal environment maintenance by its multiple functions. It plays a central role in the metabolic pathways of carbohydrates, lipids and proteins. N-Acetyl-p-benzoquinoneimine (NAPQI), is an intermediate product of acetaminophen produced in the presence of cytochrome-p450 that causes hepatic damage [2] and tubular necrosis in the kidney [3] in both humans and experimental animals [4] In this situation, a large amount of APAP is metabolized by the presence of P450s, which leads to reduced GSH levels by NAPQI conjugation and covalent binding of NAPQI. Acetaminophen’s clinical and biochemical side effects are well known and it is used as a reference compound to assess the strengths and weaknesses of genomic and proteomic technologies as toxicological tools
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