Toxic action/toxicity

Abstract

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mecha...

Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

“…In the present study, calcein-AM staining revealed that incubation of normal lymphocytes and Jurkat cells for 24 h with 600 mM CEES resulted in an approximately 60 and 80% loss of viability, respectively ( Figure 1a). Given that various toxic agents affect the intracellular concentration of GSH (Hathway, 2000), we examined the possible relevance of endogenous GSH to CEES toxicity in Jurkat cells. We incubated cells for 20 h with 200 mM L-BSO, a selective inhibitor of g-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis (Chiba et al, 1996;Oda et al, 1999), in order to deplete them of GSH.…”

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

“…The typical toxic action is the reaction of a chemical or its reactive metabolite(s) with cellular macromolecules to produce covalent binding or other chemical alterations of the substrate (54). Also, chemicals can indirectly generate other intracellular reactants, such as reactive oxygen species (12,46,139).…”

In vitro genotoxicity investigations of jet fuel

“…It is necessary to develop appropriate test systems to investigate metabolic activity on an individual and molecular level. The hepatic cell lines (H411E and Hepa1c1c7) were chosen as experimental systems due to the fact that the liver is the major site of detoxification of exogenous and endogenous compounds in the body (Hathway, 2000).…”

“…Genotoxic chemicals can be either direct acting or require metabolic activation, which normally is tissue and cell type specific (Hathway, 2000, Conney, 1982. It has been previously shown that the activities of protective enzymes as well as DNA strand break repair capabilities vary considerably between cell types (Duthie and Collins, 1997).…”

“…Even though benzene is present in the fuels and its metabolite p-benzoquinone is an established DNA damaging agent, its known effects on SCE and DNA adduct formation are not apparent in this study. However, the route of action of benzene as a mutagen is by covalently binding its reactive metabolites to cellular macromolecules, leading to oxidative DNA damage through the formation of hydroxyl radicals via hydrogen peroxide (Anderson et al, 1995, Snyder et al, 1996, Hathway, 2000, so the effects could have been detected by the oxidative comet assay. It is also possible that the DNA damaging effects of benzene are negligible due to its low concentrations in the jet fuel formulation.…”