Endotoxin Potentiates the Hepatotoxicity of Cocaine in Male Mice

Labib, Ramez; Turkall, Rita M.; Abdel‐Rahman, Mohamed S.

doi:10.1080/00984100290071252

Cited by 24 publications

(15 citation statements)

References 64 publications

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“…LPS potentiated the hepatotoxicity of cocaine, causing submassive necrosis ( Figure 3D), with a 450-and 60-fold increase in the plasma ALT and AST activities, respectively ( Figure 2). These findings are consistent with a previous study conducted in our laboratory (Labib, Turkall, and Abdel-Rahman 2002a).…”

Section: Hepatotoxicity Assessmentsupporting

confidence: 96%

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Endotoxin Potentiates Cocaine-Mediated Hepatotoxicity by Nitric Oxide and Reactive Oxygen Species

2003

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Exposure to small, noninjurious doses of the inflammagen, bacterial endotoxin (lipopolysaccharide, LPS) augments the toxicity of certain hepatotoxicants, including cocaine. The mechanism of this interaction has not been clearly elucidated, but it seems that aspects of the inflammatory response initiated by exposure to LPS may be responsible. In particular, this study examined the role of Kupffer cells and the modulating effects of nitric oxide (NO) and reactive oxygen species (ROS) on the LPS potentiation of cocaine-mediated hepatotoxicity (CMH). Mice were administered oral cocaine hydrochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 x 10(6) EU LPS/kg given intraperitoneally (IP) 4 hours after the last cocaine injection. Pretreatment regimens consisted of administration of 300 mg/kg, IP, of aminoguanidine (AM) or 1,3-dimethylthiourea (DMU) at 1 hour or 15 minutes, respectively, before each cocaine administration. In another group, mice were pretreated with saline using the same cocaine and LPS treatment protocol, but received a single pretreatment of 7 mg gadolinium chloride (GdCl(3))/kg intravenously (IV), or sterile saline 24 hours prior to the LPS administration. The GdCl(3) (Kupffer cell inhibitor) pretreatment inhibited the LPS potentiation of CMH, but did not reverse the effects of cocaine alone. On the other hand, AM (NO synthase inhibitor), decreased the synthesis of NO as observed by the decrease in the plasma nitrate/nitrite level and completely reversed the hepatotoxic effects of cocaine and LPS alone and in combination. Moreover, DMU (hydroxyl free radical scavenger) ameliorated the effects of cocaine and significantly reduced the hepatotoxicity observed with the cocaine and LPS administration. These data suggest that cocaine sensitizes the liver and subsequent activation of Kupffer cells by LPS leads to the formation of increased levels of NO, which can promote oxidant stress and thus provide an environment favoring the generation of more reactive species such as the hydroxyl free radical.

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Section: Hepatotoxicity Assessmentsupporting

confidence: 96%

“…Specifically, a small dose of LPS can dramatically potentiate the hepatotoxicity of cocaine (Labib, Turkall, and Abdel-Rahman 2002a). The purpose of this study was to determine the role oxidant stress in the LPS potentiation of CMH, specifically the contribution of Kupffer cells, the iNOS-derived NO and the hydroxyl free radical.…”

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confidence: 99%

Endotoxin Potentiates Cocaine-Mediated Hepatotoxicity by Nitric Oxide and Reactive Oxygen Species

2003

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“…Referring to the impact of cocaine on thiols homeostasis, only a few studies have shown that the administration of its relatively high doses (20–25 mg/kg) significantly increased the GSH and Cys concentrations in the rodent liver [ 33 – 36 ], but such treatment decreased GSH content in plasma [ 35 , 37 , 38 ]. Moreover, cocaine lowered glutathione peroxidase activity in the liver while it enhanced glutathione reductase activity both in the liver and plasma [ 35 – 38 ].…”

Section: Introductionmentioning

confidence: 99%

Cysteine Metabolism and Oxidative Processes in the Rat Liver and Kidney after Acute and Repeated Cocaine Treatment

et al. 2016

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The role of cocaine in modulating the metabolism of sulfur-containing compounds in the peripheral tissues is poorly understood. In the present study we addressed the question about the effects of acute and repeated (5 days) cocaine (10 mg/kg i.p.) administration on the total cysteine (Cys) metabolism and on the oxidative processes in the rat liver and kidney. The whole pool of sulfane sulfur, its bound fraction and hydrogen sulfide (H2S) were considered as markers of anaerobic Cys metabolism while the sulfate as a measure of its aerobic metabolism. The total-, non-protein- and protein- SH group levels were assayed as indicators of the redox status of thiols. Additionally, the activities of enzymes involved in H2S formation (cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3-MST) and GSH metabolism (γ-glutamyl transpeptidase, γ-GT; glutathione S-transferase, GST) were determined. Finally, we assayed the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) as markers of oxidative stress and lipid peroxidation, respectively. In the liver, acute cocaine treatment, did not change concentrations of the whole pool of sulfane sulfur, its bound fraction, H2S or sulfate but markedly decreased levels of non-protein SH groups (NPSH), ROS and GST activity while γ-GT was unaffected. In the kidney, acute cocaine significantly increased concentration of the whole pool of sulfane sulfur, reduced the content of its bound fraction but H2S, sulfate and NPSH levels were unchanged while ROS and activities of GST and γ-GT were reduced. Acute cocaine enhanced activity of the CSE and 3-MST in the liver and kidney, respectively. Repeatedly administered cocaine enhanced the whole pool of sulfane sulfur and reduced H2S level simultaneously increasing sulfate content both in the liver and kidney. After repeated cocaine, a significant decrease in ROS was still observed in the liver while in the kidney, despite unchanged ROS content, a marked increase in MDA level was visible. The repeated cocaine decreased 3-MST and increased γ-GT activities in both organs but reduced GST in the kidney. Our results show that cocaine administered at a relatively low dose shifts Cys metabolism towards the formation of sulfane sulfur compounds which possess antioxidant and redox regulatory properties and are a source of H2S which can support mitochondrial bioenergetics.

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“…Development of hepatotoxicity elicited by cocaine is also associated with reduction of GSH levels. Depletion of GSH causes liver cells to become more susceptible to lipid peroxidation and studies have shown that inhibition of oxidative metabolism attenuates cocaine mediated hepatotoxicity [29,30]. Therefore, preservation of GSH should also play a role in modulating CIH.…”

Section: Discussionmentioning

confidence: 99%

PARP-1 Inhibitor Attenuates Cocaine-Induced Hepatotoxicity

McCluskey¹

2012

TOTOXIJ

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Cocaine abuse is associated with multiple health problems including occasional hepatic failure and death. The mechanism of cocaine-induced hepatotoxicity (CIH) is not clear, although studies in mice have demonstrated that cocaine-induced liver injury may be mediated by nitric oxide and reactive oxygen species. Recently, we have found that cocaine increases poly (ADP-ribose) polymerase (PARP) activity in the liver. Therefore, inhibition of PARP may block CIH. A preliminary assessment of the PARP inhibitor 3,4-Dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) in ICR mice failed to attenuate CIH. However, the PARP inhibitor 1,5-dihydroxyisoquinoline (DIQ) successfully attenuated CIH. Mean ALT activity of 569 IU caused by cocaine treatment alone, was limited to 79 IU in ICR mice concomitantly treated with DIQ (10 mg/kg, ip). The protective effect of DIQ was also associated with prevention of development of lipid peroxidation in liver tissue, reduced depletion of glutathione (GSH), and a reduced production of nitrites. Cocaine-induced TBARS was significantly decreased by DIQ from a mean of 5.7 nmol/mg protein to a mean of 2.5 nmol/mg protein, similar to untreated mice. Hepatic GSH was reduced more than 2 fold following cocaine administration but treatment with DIQ conserved GSH at the level of untreated mice. The protective effect of DIQ in attenuating CIH can potentially be explained by the dual inhibitory effect of DIQ that reduces induction of PARP and inducible nitric oxide synthetase (iNOS). The DIQ attenuation of CIH provides evidence for a PARP and iNOS modulated mechanism of action for this hepatocellular pathology.

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Endotoxin Potentiates the Hepatotoxicity of Cocaine in Male Mice

Cited by 24 publications

References 64 publications

Endotoxin Potentiates Cocaine-Mediated Hepatotoxicity by Nitric Oxide and Reactive Oxygen Species

Endotoxin Potentiates Cocaine-Mediated Hepatotoxicity by Nitric Oxide and Reactive Oxygen Species

Cysteine Metabolism and Oxidative Processes in the Rat Liver and Kidney after Acute and Repeated Cocaine Treatment

PARP-1 Inhibitor Attenuates Cocaine-Induced Hepatotoxicity

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