Toxicity postulated mechanisms

Here, a new model of hematologic toxicity of anticancer agents is introduced. The postulated mechanisms that influence the response variable (e.g., neutrophil count) are ... 

Nefazodone can cause myositis and rhabdomyolysis in patients taking pravastatin and simvastatin (25). The postulated mechanism involves inhibition of CYP3A4, leading to reduced clearance of the HMG-CoA reductase inhibitors and muscle toxicity. 

An alternative postulated mechanism of AmB induced cell damage involves oxidative stress with the formation of free radical intermediates [15,16, 79]. Evidence against this hypothesis has been provided by recent studies that evaluated the anti- or pro-oxidant effects of AmB by examining its effects on phospholipid pattern in aortic smooth muscle cells [80] as well as on lipid-peroxidation of cis-Parinaric acid in liposomes [81]. These studies provided evidence for an antioxidant role for AmB rather than a pro-oxidant role and suggesting that oxidative stress is not involved in AmB-induced toxicity. 

Blockade of the cardiac H-2 receptors is the postulated mechanism for the cardiovascular toxicity associated with cimetidine overdosage. Cimetidine penetrates the blood-brain barrier and is associated with central nervous system effects in predisposed individuals, including elderly, and patients with poor renal function. 

The pathogenesis of drug-induced pancreatitis does not appear to differ from other causes of AP. Exactly how medications induce AP is unknown, but postulated mechanisms include immune-mediated inflammatory response, direct cellular toxicity, pancreatic duct... 

Studies of the concomitant use of azithromycin with carbamazepine, terfenadine, and zidovudine have not reported drug interactions [131-133]. With the potential exception of antacids, no drug interactions have been reported with azithromycin, which does not appear to be metabolized by the cytochrome P-450 system [4, 134], Both azithromycin and clarithromycin have been associated with digoxin toxicity. The postulated mechanism is by eradication of Eubacterium lentum, an anaerobic gram-positive bacteria responsible for the metabolism of digoxin in some patients [43]. 

Figure 1. Postulated mechanisms of toxicity by chemically reactive metabolites...

While pain after photorefractive keratectomy needs to be treated effectively, the non-prescribed long-term misuse of local anesthetics can lead to impaired wound healing. Postulated mechanisms include inhibition of corneal epithelial migration and adhesion and toxic effects on stromal keratocytes [49 , 50 ]. 

Postulated mechanism for hydrazine toxicity. Previous work (11) has provided evidence that acetylhydrazine is the metabolite of ioniazid and that isopropylhydrazine is the metabolite of... 

The exact mechanism for the toxic effects of organic arsenicals is unknown. DNA alkylation and/or inhibition of GSH-scavenging pathways are two postulated mechanisms (Nesnow et al., 2002). On contact with arsenicals, a blistering reaction occurs on skin, eye, or pulmonary tissues (Cohen et al., 2006 Devesa et al., 2006 Kojima et al., 2006). Animal data and limited human trials suggest that organic arsenicals readily penetrate tire skin. Within seconds of contact, the chemical fixes itself to the epidermis and dermis. Pain is immediate, followed by destruction of subcutaneous tissue. The separation of dermis from epidermis and capillary leakage cause fluid-filled vesicles (McManus and Huebner, 2005 Naranmandura and Suzuki, 2008). Intravascular hemolysis of erythrocytes with subsequent hemolytic anemia may result (Wu et al., 2003). 

The second mode of toxicity is postulated to involve the direct interaction of the epidithiodiketopiperazine motif with target proteins, forming mixed disulfides with cysteine residues in various proteins. Gliotoxin, for example, has been demonstrated to form a 1 1 covalent complex with alcohol dehydrogenase [13b, 17]. Epidithiodi-ketopiperazines can also catalyze the formation of disulfide bonds between proxi-mally located cysteine residues in proteins such as in creatine kinase [18]. Recently, epidithiodiketopiperazines have also been implicated in a zinc ejection mechanism, whereby the epidisulfide can shuffle disulfide bonds in the CHI domain of proteins, coordinate to the zinc atoms that are essential to the tertiary structure of that domain, and remove the metal cation [12d, 19],... 

Bromoethylamine (11.133, R = Br, Fig. 11.18) is a potent nephrotoxin used to create an experimental model of nephropathy. Its mechanism of toxicity is postulated to involve perturbation of mitochondrial function, and its metabolism was investigated in a search for toxic metabolites. In rat plasma, 2-bromoethylamine was converted to aziridine (11.134), formed by intramolecular nucleophilic substitution and bromide elimination [155], Another major metabolite was oxazolidin-2-one (11.136). This peculiar metabolite resulted from the reaction of 2-bromoethylamine with endogenous carbonate to form carbamic acid 11.135, followed by cyclization-elimination to oxazoli-din-2-one. In aqueous media containing excess carbonate, the formation of... 

The clinical effects of chloroform toxicity on the central nervous system are well documented. However, the molecular mechanism of action is not well understood. It has been postulated that anesthetics induce their action at a cell-membrane level due to lipid solubility. The lipid-disordering effect of chloroform and other anesthetics on membrane lipids was increased by gangliosides (Harris and Groh 1985), which may explain why the outer leaflet of the lipid bilayer of neuronal membranes, which has a large ganglioside content, is unusually sensitive to anesthetic agents. Anesthetics may affect calcium-dependent potassium conductance in the central nervous system (Caldwell and Harris 1985). The blockage of potassium conductance by chloroform and other anesthetics resulted in depolarization of squid axon (Haydon et al. 1988). 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

Several mechanisms have been postulated to account for thallium s toxicity, including ligand formation with sulfhydryl groups of enzymes and transport proteins, inhibition of cellular respiration, interaction with riboflavin and riboflavin-based cofactors, alteration of the activity of K -dependent proteins, and disruption of intracellular calcium homeostasis. ... 

Our studies indicate that rapid metabolic detoxification of linear furanocoumarins is an effective resistance mechanism for K polyxenes against the toxic effects of these compounds. It has been postulated that the adaptation of some plants to produce angular furanocoumarins was in response to the reduced effectiveness of the linear furanocoumarins as deterrents for herbivores such as polyxenes (22). Such may Indeed be true, but our studies on the comparative detoxification of linear and angular furanocoumarins suggest that, at best, the presence of angular furanocoumarins in plants confers only a tenuous margin of relative "safety" against polyxenes. 

The authors postulated that iodide toxicity had resulted in hemolysis and hemoglobinuria, which, together with acute interstitial nephritis secondary to inhibition of prostaglandin synthesis from mefenamic acid ingestion, had resulted in acute renal insufficiency. The mechanism of hemolysis resulting from toxic doses of iodine is not clear, although it may reflect inhibition of various red cell enzymes. 

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