Chlorinated Methanes and Liver Injury: Highlights of the Past 50 Years

Abstract

The chlorinated methanes, particularly carbon tetrachloride and chloroform, are classic models of liver injury and have developed into important experimental hepatoxicants over the past 50 years. Hepatocellular steatosis and necrosis are features of the acute lesion. Mitochondria and the endoplasmic reticulum as target sites are discussed. The sympathetic nervous system, hepatic hemodynamic alterations, and role of free radicals and biotransformation are considered. With carbon tetrachloride, lipid peroxidation and covalent binding to hepatic constituents have been dominant themes over the years. Potentiation of chlorinated methane-induced liver injury by alcohols, aliphatic ketones, ketogenic compounds, and the pesticide chlordecone is discussed. A search for explanations for the potentiation phenomenon has led to the discovery of the role of tissue repair in the overall outcome of liver injury. Some final thoughts about future research are also presented.

Common Solvent Toxicity: Autoxidation of Respiratory Redox-Cyclers Enforced by Membrane Derangement

“…This view coheres with the fo cus of current scientific endeavour being on m eta bolic activation, even though the "putative chemi cal species in most cases ... has not necessarily been identified" (Plaa, 2000).…”

“…Exposure of mito chondria to toluene leads to accumulation of tolu ene in the membrane, causing derangement of the molecular order of the phospholipid bilayer, and increased membrane fluidity. A decrease of extramitochondrial proton accumulation suggests in- (Sikkema et al, 1995) membrane toxicity in microorganisms (Sikkema et al, 1995) sudden death following recreational inhalation of propane, »-butane or iso butane (Rohrig, 1997) generation of hydroxyl radical in fresh meat (Karam and Simic, 1989) euphoria, sudden death, injury to liver, kidneys and brain (Flanagan and Ives, 1994) superoxide by autoxidation of ubisemiquinone in isolated mitochondria (Nohl et al, 1996) membrane derangement and proton penetration (Sikkema et al, 1992) enhanced alkylhydroperoxide reductase subunit C (AhpC) activity in resistant Escherichia coli (Ferrante et al, 1995) hemolysis in ponies (Paradis et al, 1991) induction of AhpC in E. coli K12 and overproduction of A hpC in indoleresistant E. coli variant (G arbe et al, 2000a) generates active oxygen and superoxide (Kodama et al, 1997) induction of superoxide dismutase in E. coli (Zhang and Yonei, 1991) membrane derangement and lysis of human erythrocytes (Verma and Singhal, 1991) lipid peroxidation in rat testes (Samanta et al, 1999) neuroactive PCBs disruptive of mitochondrial oxidative energy production (Maier et al, 1994) neuroactive PCBs produced oxidants in rat synaptosomes (Voie and Fonnum, 2000) euphoria, sudden death, injury to liver, kidneys and brain (Flanagan and Ives, 1994) vasodilation, cardiac arrest (sudden death), hemolytic anemia (reviewed by Tse et al, 1990) lipid peroxidation (Channel et al, 1998, Toraason et al, 1999, Plaa, 2000 oxidative DNA damage (Toraason et al 1999) alteration of mitochondrial structure by chloroform (Guastadisegni et al, 1999) generation of hydroxyl radical in white and red muscle meat (Karam and Simic, 1990) euphoria, nitric oxide release causative of smooth muscle relaxation and N-nitrosamine formation, methemoglobinemia (Maikel, 1988;Hecht, 1997) lipid peroxidation in liver, lung and kidney...…”

Northern Exposures, Northern Risks: Toxicology in Canada

“…Plaa's research work has included studies of chlorinated hydrocarbon hepatotoxicity and its potentiation by aliphatic ketones (14). Dr. Plaa has also been a tireless advocate for the professional development of toxicologists, through the Society of Toxicology, International Union of Toxicology (IUTOX), and Society of Toxicology of Canada (STC) (15 and developed a successful program in both environmental and clinical toxicology research.…”

Comparative Study of the Antioxidative Activity of Culinary Herbs and Spices, and Hepatoprotective Effects of Three Selected Lamiaceae Plants on Carbon Tetrachloride-Induced Oxidative Stress in Rats

“…Carbon tetrachloride (CCl 4 )-induced liver injury is an oxidative-stress model used for screening hepatoprotective materials (McCay et al, 1984;Recknagel et al, 1989;Plaa, 2000;Weber et al, 2003 (Deshpande et al, 1998;Sotelo-Félix et al, 2002;Botsoglou et al, 2008;Park, 2010;Farhoudi, 2011). However, in general, many of the phytonutrients in foods that possess biological activities are also unpalatable because of bitter tastes and odors (Drewnoski and Gomez-Carneros, 2000;Lesschaeve and Noble, 2005;Soares et al, 2013).…”

“…Carbon tetrachloride (CCl 4 )-induced liver injury is an oxidative-stress model used for screening hepatoprotective materials (McCay et al, 1984;Recknagel et al, 1989;Plaa, 2000;Weber et al, 2003). (Deshpande et al, 1998;Sotelo-Félix et al, 2002;Botsoglou et al, 2008;Park, 2010;Farhoudi, 2011).…”