Protection against Acetaminophen Hepatotoxicity by a Single Dose of Clofibrate: Effects on Selective Protein Arylation and Glutathione Depletion

Manautou, José E.; Hart, Susan; Khairallah, Edward A.; Cohen, Steven D.

doi:10.1093/toxsci/29.2.229

Cited by 8 publications

(9 citation statements)

References 24 publications

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“…First, covalent binding of 14 C‐APAP was not different between DB and non‐DB mice. Second, selective protein arylation of cytosolic acetaminophen binding proteins, which has served as an indirect indicator of net availability of reactive electrophile in the liver, was also similar between non‐DB and DB mice (11, 38). Third, the degree of GSH depletion was also similar between non‐DB and DB mice, further strengthening the observation that equal bioactivation occurred in both groups.…”

Section: Discussionmentioning

confidence: 99%

Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

et al. 2003

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Diabetic (DB) mice exhibit significant resistance to hepatotoxicants. The role of peroxisome proliferator receptor (PPAR)-alpha activation in diabetes, in protection against lethal acetaminophen (APAP) challenge, was investigated. Upon treatment with APAP (600 mg/kg, i.p., a LD100 dose in wild-type [WT] non-DB mice), WT-DB mice showed only 30% mortality and 40% less liver injury as measured by alanine aminotransferase and histopathology. In contrast, diabetes in PPAR knockout (PPAR-alpha-/-) mice failed to protect against APAP toxicity, suggesting the importance of PPAR-alpha in diabetes-induced protection. S-phase DNA synthesis and PCNA immunohistochemical staining after injury showed early and robust tissue repair in WT-DB mice, but not in the PPAR-alpha-/--DB mice. Microarray analyses were performed on livers from non-DB and DB (WT and PPAR-alpha-/-) mice at 0 and 12 h after APAP. Microarray data were confirmed via real-time polymerase chain reaction analysis of several genes, including stress response, immediate early genes, DNA damage, heat shock proteins, and cell cycle regulators, followed by Western analyses of selected proteins. Gel shift assays revealed higher activation of nuclear factor-kappaB in WT-DB mice after APAP treatment. These findings suggest PPAR-alpha activation as a hepatoprotective adaptive response mediating protection against APAP in diabetes.

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Section: Discussionmentioning

confidence: 99%

Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

et al. 2003

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“…Livers were homogenized (10% w/v) in a buffer containing 0.25 M sucrose, 10 mM Tris-HCl, 1 mM MgCl 2 , pH 7.4 (STM buffer). Homogenates were centrifuged at 9000 ϫ g. The resultant supernatant was centrifuged at 105,000 ϫ g for 1 h (Manautou et al, 1994(Manautou et al, , 1996. Cytosolic fractions were collected and stored at -80 0 C until needed.…”

Section: Assessment Of Selective Protein Arylation Due To Apapmentioning

confidence: 99%

Type 1 Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity

Shankar

Vaidya²,

Apte³

et al. 2003

Toxicological Sciences

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Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.

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“…Interestingly it has been reported that flavonoids and saponins which are present in Ph.Cr also activates PPAR-α system contributing in prevention of CCL 4 and paracetamol-induced hepatotoxicity [19,20]. This mechanism of activating PPAR-α system could be attributed to role of flavonoids and saponins present in Parthenium hysterophorus, playing role in prevention of CCL 4 and paracetamol-induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of <i>Parthenium hysterophorus</i> against carbon tetrachloride- and paracetamol-induced hepatotoxicity in rabbits

Saleem¹,

Naureen²,

Khan³

et al. 2018

Trop. J. Pharm Res

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To investigate the possible hepatoprotective potential of Parthenium hysterophorus crude extract (Ph.Cr) against carbon tetrachloride (CCL4)-and paracetamol-induced hepatotoxicity in rabbits. Methods: Twenty rabbits were divided into five groups of four rabbits each. Group 1 served as normal control and received normal saline (5 mL/kg). Group 2 received normal saline followed by CCL4 (0.75 mL/kg p.o dose) after 1 h. Groups 3 and 4 received Ph.Cr at doses of 15 and 30 mg/kg po, respectively, for 7 days followed by one dose of CCL4, 2 h after the last extract dose (0.75 mL/kg, sc). Group 5 received silymarin as reference standard at a dose of 100 mg/kg orally for 7 days followed by one dose of CCL4 (0.75 mL/kg, sc), 2 h after the last drug dose. The effect of the extract on potassium (K +)induced contractions in isolated rabbit jejenum was also evaluated. At the end of the study, the animals were sacrificed and their liver architecture examined microscopically. Results: Pre-treatment of rabbits with Ph.Cr reduced ALT, ALP and TB levels (p < 0.05, p < 0.01, p < 0.001) dose dependently. Hepatoprotective data indicate that Ph.Cr markedly reduced CCL4-and paracetamol-induced toxicity by preserving the histological architecture of the liver tissue at near normal. In isolated rabbit jejunum tissue, Ph.Cr relaxed high K + (80 Mm)-induced contractions in a concentration-dependent (0.03-10 mg/mL) manner like that caused by silymarin. Conclusion: In the light of the results obtained, Parthenium hysterophorous possesses hepatoprotective activity against CCL4-and paracetamol-induced hepatic damage, possibly mediated via its antioxidant and Ca ++ antagonist mechanisms.

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Protection against Acetaminophen Hepatotoxicity by a Single Dose of Clofibrate: Effects on Selective Protein Arylation and Glutathione Depletion

Cited by 8 publications

References 24 publications

Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

Activation of PPAR‐α in streptozotocin‐induced diabetes is essential for resistance against acetaminophen toxicity

Type 1 Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity

Protective effect of <i>Parthenium hysterophorus</i> against carbon tetrachloride- and paracetamol-induced hepatotoxicity in rabbits

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