Metabolism toxin binding

Table III describes the characteristics of the test substance to be considered. Although in the case of carcinogenesis, we do not know the mechanisms involved, there are inherent biological and chemical properties which can indicate limits to the potential reactivity of chemicals with mammalian cell constituents. These include chemical similarity to other known toxins, binding or adduct formation with cell macromolecules, genotoxicity or activity in short-term tests for carcinogenicity, metabolic and pharmacokinetic data, and other pertinent physiological, pharmacological or biochemical properties.

By interfering with any one of the many phases associated with these second messenger pathways, toxins may alter channel gating. For example, the blue green algal toxins, aplysiatoxin, and lyngbyatoxin bind to and activate protein kinase C in a manner similar to phorbol esters (73). They also stimulate arachidonic acid metabolism (74). The coral toxin, palytoxin, also stimulates arachidonic acid breakdown albeit by an unknown mechanism (74) and affects other biochemical activities of the cell (see chapters by Fujiki et al., Wattenberg et al., and Levine et al., this volume). 

Another aspect to be considered is the reversibility of a toxic effect. In most cases, toxicity induced by a chemical is essentially reversible. Unless damage to the affected organs has progressed too far, so as to threaten the survival of the organism, the individual will recover when the toxin is removed by excretion or inactivated by metabolism. However, in some cases the effect may outlast the presence of the toxin in the tissue. A typical example of such an effect is intoxication with organophos-phates, which bind essentially irreversibly to acetylcholine esterase. 

Unfortunately, the outcome of oxidation is not only dependent on the ease with which it will occur (susceptibility) but is also dependent on the overall lipophilicity of the molecule (see Section 2.3.1). The enzymes most frequently implicated in the transformation of compounds to reactive toxins are the cytochrome P450s. Because the determinants of binding (lipophilicity, steric complementarity, presence of polar functions) vary in importance across the various P450 isoenzymes, the outcome of metabolism is currently much more difficult to predict than the susceptibility. 

The carcinogenicity of af la toxin is reduced by protein deficiency, presumably because of reduced metabolic activation to the epoxide intermediate, which may be the ultimate carcinogen, which binds to DNA (Fig. 5.14). A deficiency in dietary fatty acids also decreases the activity of the microsomal enzymes. Thus, ethylmorphine, hexobarbital, and aniline metabolism are decreased, possibly because lipid is required for cytochromes P-450. Thus, a deficiency of essential fatty acids leads to a decline in both cytochromes P-450 levels and activity in vivo. 

The metabolism of zinc is influenced by hormones, stress situations, lipopolysaccharides, toxins, oxygen radicals, lipid peroxidations, etc. This may lead to fluctuations in the zinc concentration, mainly due to the induction of metallothioneine (MT), which is a transport and intracellular depot protein. One third of this protein consists of cysteine, which binds zinc, copper, cadmium, cobalt and mercury. This protects the body from toxic heavy metal... 

Cyanide is described as a cellular toxin because it inhibits aerobic metabolism. It reversibly binds with ferric (Fe " ") iron-containing cytochrome oxidase and inhibits the last step of mitochondrial oxidative phosphorylation. This inhibition halts carbohydrate metabolism from citric acid cycle, and intracellular concentrations of adenosine triphosphate are rapidly depleted. When absorbed in high enough doses, respiratory arrest quickly ensues, which is probably caused by respiratory muscle failure. Cardiac arrest and death inevitably follow. 

There is evidence supporting a role for hepatic damage by intravascular proteases in the pathogenesis of neonatal hepatic disease, as reviewed in the previous edition of this textbook,The AAT deposits in the hepatic endoplasmic reticulum do not bind normally to calnexin, one of the chaperones for protein synthesis and release it is known that proteolytic enzymes reduce the activity of intracellular, membrane-bound proteins involved in metabolic processes. An additional component in congenital and neonatal hepatic disease may be exposure to maternal estrogens, which increase susceptibility to damage from hepatitis viral infections and some toxins. 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

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