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

International Journal of Toxicology - Tập 22 Số 4 - Trang 305-316 - 2003
Ramez Labib1, Rita M. Turkall2, Mohamed S. Abdel‐Rahman3
1Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA
2Department of Clinical Laboratory Sciences, School of Health Related Professions, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
3Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA

Tóm tắt

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 hy-drochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 times 106 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 (Gd Cl3)/kg intravenously (IV), or sterile saline 24 hours prior to the LPS administration. The Gd Cl3 (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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International Journal of Toxicology

Tập 22 Số 4

305-316

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