Microsomal oxidative damage promoted by acetaminophen metabolism

Letelier, María Eugenia; López-Valladares, Miguel; Peredo-Silva, Liliana; Rojas-Sepúlveda, Daniel; Aracena-Parks, Paula

doi:10.1016/j.tiv.2011.04.022

Cited by 31 publications

(17 citation statements)

References 27 publications

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“…At 24 hours after the last METH injection, the damage escalated to severe global, cytoplasmic disappearance (Figure 1), suggestive of autophagy (Rautou et al, 2008). Although the mechanisms by which METH causes hepatotoxicity were not evaluated, the findings are consistent with reports that the metabolism of METH by the liver via the 2D6 p450 enzymes (Lin et al, 1997) may promote hepatocellular damage (Pourahmad et al, 2010, Letelier et al, 2011). Furthermore, amphetamines have been shown to cause hepatocellular mitochondrial damage (Moon et al, 2008).…”

Section: Discussionsupporting

confidence: 85%

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Halpin

Yamamoto

2012

J. Neurosci.

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Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466, an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules.

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Section: Discussionsupporting

confidence: 85%

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Halpin

Yamamoto

2012

J. Neurosci.

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“…; Letelier et al. ). METH has also been shown to have extensive effects on cardiovascular function, causing both cardiac dysfunction and widespread vasospasm (Wang et al.…”

Section: Discussionmentioning

confidence: 98%

Methamphetamine causes acute hyperthermia‐dependent liver damage

Halpin

Gunning

Yamamoto

2013

Pharmacology Res & Perspec

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Methamphetamine-induced neurotoxicity has been correlated with damage to the liver but this damage has not been extensively characterized. Moreover, the mechanism by which the drug contributes to liver damage is unknown. This study characterizes the hepatocellular toxicity of methamphetamine and examines if hyperthermia contributes to this liver damage. Livers from methamphetamine-treated rats were examined using electron microscopy and hematoxylin and eosin staining. Methamphetamine increased glycogen stores, mitochondrial aggregation, microvesicular lipid, and hydropic change. These changes were diffuse throughout the hepatic lobule, as evidenced by a lack of hematoxylin and eosin staining. To confirm if these changes were indicative of damage, serum aspartate and alanine aminotransferase were measured. The functional significance of methamphetamine-induced liver damage was also examined by measuring plasma ammonia. To examine the contribution of hyperthermia to this damage, methamphetamine-treated rats were cooled during and after drug treatment by cooling their external environment. Serum aspartate and alanine aminotransferase, as well as plasma ammonia were increased concurrently with these morphologic changes and were prevented when methamphetamine-induced hyperthermia was blocked. These findings support that methamphetamine produces changes in hepatocellular morphology and damage persisting for at least 24 h after drug exposure. At this same time point, methamphetamine treatment significantly increases plasma ammonia concentrations, consistent with impaired ammonia metabolism and functional liver damage. Methamphetamine-induced hyperthermia contributes significantly to the persistent liver damage and increases in peripheral ammonia produced by the drug.

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“…Direct application of acetaminophen to the bath in patch clamping or Ca 2+ imaging experiments had no acute effect on membrane currents or [Ca 2+ ] cyt . Oxidant stress caused by ROS and RNS formed in the liver in acetaminophen overdose is considered a major mediator of hepatocellular death (23). To determine whether hepatocytes express ROS-sensitive Ca 2+ -permeable channels which can potentially be activated by ROS and RNS generated in hepatocytes treated with acetaminophen, we used Ca 2+ imaging and patch clamping of isolated rat hepatocytes treated with H 2 O 2 .…”

Section: +mentioning

confidence: 99%

TRPM2 channels mediate acetaminophen-induced liver damage

Kheradpezhouh

Morphett

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

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Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca 2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca 2+ concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca 2+ rise. Here we report that the channel responsible for Ca 2+ entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H 2 O 2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H 2 O 2 . In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wildtype mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

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Microsomal oxidative damage promoted by acetaminophen metabolism

Cited by 31 publications

References 27 publications

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Methamphetamine causes acute hyperthermia‐dependent liver damage

TRPM2 channels mediate acetaminophen-induced liver damage

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