Reduction of Toxic Metabolite Formation of Acetaminophen

Hazai, Eszter; Vereczkey, L.; Monostory, Katalin

doi:10.1006/bbrc.2002.6541

Cited by 131 publications

(80 citation statements)

References 22 publications

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“…Therefore, it would be reasonable to assume that the difference in basal expression levels of Cyp3A13 between young and adult rats accounts for the difference in susceptibility to APAP toxicity. Cyp2E1 is another enzyme responsible for biotransformation, i.e., inhibition of Cyp2E1 decreased the production of a reactive metabolite in the liver microsome from humans (Hazai et al, 2002), although this enzyme did not show an age-difference. Based on the present results, participation of CYP3A is considered to be larger than that of CYP2E in the rat.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

et al. 2006

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-In order to verify the influence of the rat age on hepatotoxicity, male Sprague-Dawley rats of 6 (young) and 12 (adult) weeks of age were orally administered acetaminophen (APAP), isoniazid (INH), or carbon tetrachloride (CCl4). Liver samples were obtained in a time-course manner, and changes in gene expression examined by an Affymetrix GeneChip. APAP caused more prominent hepatic injury with respect to pathology and blood biochemistry in adults than in young rats, whereas no obvious agerelated differences were observed in INH-or CCl4-treated rats. Comparing gene expression in control rats, CYP3A13 was higher and GSTY2c was lower in adults, suggesting that production of the active metabolite of APAP is higher and its detoxification is lower in adults. The total amount of glutathione and total SH in rat liver was found to be higher in adult rats whereas the extent of its reduction by APAP was larger in adults. A detailed analysis of genes showing age-related differences revealed that some of them were different not in their extent but in their time course, i.e., the stress responses occurred earlier in the young than in the adult, resulting in a difference at 24 hr after dosing. These results suggest that the age-related difference in toxicity would be attributed to a higher expression of CYP3A13, producing the active metabolite of APAP as well as the lower expression of the detoxification enzyme, GSTY2c, in adult rats. Furthermore, these differences affect the time course of APAP toxicity. The present study clearly depicts the advantage of the multi-time, multi-dose protocol employed in our project for analyzing the mechanism of toxicity by gene expression profiling.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

et al. 2006

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“…The ROS, NO and NAPQI generated during APAP bioactivation binds covalently and enhanced auto-oxidation of macromolecules (proteins and lipids) of the hepatocytes plasma membranes. This subsequently induces cell membrane damage, perturbs Ca 2þ homeostasis in the mitochondrial, alters enzyme activities, and consequently results in hepatic injury or necrosis (Hazai et al 2002). When these happen, cytosolic AST, ALT, ALP and GGT are released into systemic circulation and their measurement can be used to assess the extent of drug-induced hepatotoxicity (Jaeschke et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Zea mays, Stigma maydisprevents and extenuates acetaminophen-perturbed oxidative onslaughts in rat hepatocytes

Sabiu

Hendrik

Tom

2016

Pharmaceutical Biology

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Context: Zea mays L. (Poaceae) Stigma maydis is an underutilized product of corn cultivation finding therapeutic applications in oxidative stress-related disorders. Objectives: This study investigated its aqueous extract against acetaminophen (APAP)-perturbed oxidative insults in rat hepatocytes. Materials and methods: Hepatotoxic rats were orally pre-and post-treated with the extract (at 200 and 400 mg/kg body weight) and vitamin C (200 mg/kg body weight), respectively, for 14 days. Liver function, antioxidative and histological analyses were thereafter evaluated. Results: The APAP-induced marked (p < 0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and the concentrations of bilirubin, oxidized glutathione, protein carbonyls, malondialdehyde, conjugated dienes, lipid hydroperoxides and fragmented DNA were dose-dependently extenuated in the extract-treated animals. The extract also significantly (p < 0.05) improved the reduced activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase as well as total protein, albumin and glutathione concentrations in the hepatotoxic rats. These improvements may be attributed to the bioactive constituents as revealed by the gas chromatography-mass spectrometric chromatogram of the extract. The observed effects compared favourably with vitamin C and are informative of hepatoprotective and antioxidative attributes of the extract and were further supported by the histological analysis. Conclusion: The data from the present findings suggest that Stigma maydis aqueous extract is capable of preventing and ameliorating APAP-mediated oxidative hepatic damage via enhancement of antioxidant defence systems. ARTICLE HISTORY

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“…Paracetamol is metabolized in the liver to excretable glucuronide conjugates dose of this drug results in the accumulation of a toxic m tabolite known as N -acetyl (NAPQI) [14]. This metabolite induces t to proteins and DNA to produce protein responsible for the dysfunction and death of hepatocytes leading to liver necrosis [15]. mol -induced liver damage hepatoprotective potential of plant extracts [ In this study, the evidence of paracetamol injury was the elevation of blood levels of cellular markers (AST, ALT, ALP and TBIL) and decreased levels of alb min and total proteins.…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective Activity of Ocimum americanum L Leaves against Paracetamol − Induced Liver Damage in Rats

Aluko¹

2013

AJLS

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This study was designed to investigate the hepatoprotective activity of aqueous extract of Ocimum americanum leaves against paracetamol -induced liver damage in rats. Hepatic damage was induced by paracetamol. Thereafter, the levels of some serum biochemical parameters such as alanine trasaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), albumin, total bilirubin (TBIL) and total protein (TP) were investigated. The activities of ALP, AST, ALT and histological changes in the liver of rats were also determined. Silymarin was used as the standard hepatoprotective drug. The pre -treatment of rats with aqueous extract of O. americanum leaves caused a significant increase in the serum levels of TP and albumin. There was a significant decrease in the serum levels of ALP, AST, ALT and TBIL with a corresponding increase in the activities of ALP, AST and ALT in the liver of extract treated rats. The hepatoprotection was confirmed by histological examinations of liver sections of normal and treated rats. Furthermore, rats intoxicated with paracetamol alone had their serum ALP, AST, ALT and TBIL levels significantly increased, while TP and albumin concentrations decreased when compared with the normal rats. The aqueous extract of Ocimum americanum leaves at doses of 200 and 400 mg /kg p.o. have significant hepatoprotective ability against paracetamol -induced hepatic damage in rats.

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Reduction of Toxic Metabolite Formation of Acetaminophen

Cited by 131 publications

References 22 publications

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

Gene Expression Profile in Liver of Differing Ages of Rats After Single Oral Administration of Acetaminophen

Zea mays, Stigma maydisprevents and extenuates acetaminophen-perturbed oxidative onslaughts in rat hepatocytes

Hepatoprotective Activity of Ocimum americanum L Leaves against Paracetamol − Induced Liver Damage in Rats

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