Biochemical basis

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The development of malathion in 1950 was an important milestone in the emergence of selective insecticides. Malathion is from one-half to one-twentieth as toxic to insects as parathion but is only about one two-hundredths as toxic to mammals. Its worldwide usage in quantities of thousands of metric tons in the home, garden, field, orchard, woodland, on animals, and in pubHc health programs has demonstrated substantial safety coupled with pest control effectiveness. The biochemical basis for the selectivity of malathion is its rapid detoxication in the mammalian Hver, but not in the insect, through the attack of carboxyesterase enzymes on the aUphatic ester moieties of the molecule. 

Reviews on the occurrence, biochemical basis, and treatment of lead toxicity in children (11) and workers (3,12,13) have been pubhshed. Approximately 17% of all preschool children in the United States have blood lead levels >10 //g/dL. In inner city, low income minority children the prevalence of blood lead levels >10 //g/dL is 68%. It has been estimated that over two million American workers are at risk of exposure to lead as a result of their work. PubHc health surveillance data document that each year thousands of American workers occupationally exposed to lead develop signs and symptoms indicative of... 

The biochemical basis for the toxicity of mercury and mercury compounds results from its ability to form covalent bonds readily with sulfur. Prior to reaction with sulfur, however, the mercury must be metabolized to the divalent cation. When the sulfur is in the form of a sulfhydryl (— SH) group, divalent mercury replaces the hydrogen atom to form mercaptides, X—Hg— SR and Hg(SR)2, where X is an electronegative radical and R is protein (36). Sulfhydryl compounds are called mercaptans because of their ability to capture mercury. Even in low concentrations divalent mercury is capable of inactivating sulfhydryl enzymes and thus causes interference with cellular metaboHsm and function (31—34). Mercury also combines with other ligands of physiological importance such as phosphoryl, carboxyl, amide, and amine groups. It is unclear whether these latter interactions contribute to its toxicity (31,36). 

M. R. Juchau, ed.. The Biochemical Basis of Chemical Teratogenesis, Elsevier/North Holland, New York, 1981. 

The biochemical basis for its action in fungi has not been totally elucidated. Giclopiroxolamine [41621 -49-2] is used mainly in the treatment of mycoses of the skin and nails. 

The biochemical basis of penicillin action continues to be an area of active investigation. Penicillins are highly specific inhibitors of enzyme(s) involved in the synthesis of the bacterial cell wall, a structure not present in mammalian cells. Three principal factors are thought to be important for effective antibacterial action by a penicillin ... 

The mechanisms by which the growth supplements in serum-free medium act are still not understood. In order to achieve an understanding of the biochemical basis for the hormonal and growth factor requirements of animal cells, the basic mechanism of action of hormones and growth factors must be determined. The biochemical basis for the nutritional requirements of animal cells can only be determined when we have an understanding of the metabolism of the different types of animal cells. 

Heliantholysin. The major form of heliantholysin is a basic polypeptide chain (pi in the region of 9.8) having a molecular weight of 16,600. Its amino acid sequence has been determined (11). It is powerfully hemolytic for washed erythrocytes derived from a variety of animals, those of the cat being the most sensitive, and those of the guinea pig the most resistant (10). As is true of most hemolytic systems, the biochemical basis for the very large differences in sensitivity of erythrocytes from different animal species is unknown. 

Brownlee, M., Cerami, A. and Vlassara, H. (1988). Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J. Med. 318, 1315-1321. 

Mustafa, M.G. (1990). Biochemical basis of ozone toxicity. Free Radic. Biol. Med. 9, 245-265. 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

Biochemical Basis of the Mass Spectral Information in Bacterial ESMS... 

Wetmur JG Mount Sinai School of Medicine, New York, NY Biochemical basis for the differential genetic susceptibility of individuals to lead exposure (transgenic mice, humans) National Institute of Environmental Health Sciences... 

Cooper J., Bloom F., Roth R. (2002). The Biochemical Basis of Neuropharmacology. 8th ed. New York Oxford University Press. 

In summary, the discovery of biopharmaceuticals, in most cases, merely relates to the logical application of our rapidly increasing knowledge of the biochemical basis of how the body functions. These substances could be accurately described as being the body s own pharmaceuticals. Moreover, rapidly expanding areas of research, such as genomics and proteomics, will likely hasten the discovery of many more such products, as discussed below. 

Shapiro, L.E., Uetrecht, J., and Shear, N.H. Minocycline, perinuclear antineutrophilic cytoplasmic antibody and pigment The biochemical basis, J. Amer. Acad. Dermatol., 45, 787, 2001... 

Button, D. K. (1991). Biochemical basis for whole-cell uptake kinetics specific affinity, oligotrophic capacity, and the meaning of the Michaelis constant, Appl. 

McGuire J, Hendee J. 1971. Biochemical basis for depigmentation of skin by phenolic germicides. J Invest Dermatol 57 256-261. 

H. Koenig, A. Patel, Biochemical Basis For Fluorouracil Neurotoxicity. The Role of Krebs Cycle Inhibition by Fluoroacetate , Arch. Neurol. 1970, 23, 155-160. 

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