Biochemical basis for the toxic

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). 

The biochemical basis for the toxicity of mercury and mercury compounds resulls from its ability to form covalent bonds with sulfur. Even In low coiiccninilinns divalent mercury is capable of inaelivaiing enzymes containing suirhydrvl I —Nil) groups, causing iiileil crcncc with cellular metabolism and function. 

The biochemical basis for the toxic action of pentavalent arsenic compounds is known with less certainty. A speculation is that such arsenicals compete with phosphate in phosphorylation to form unstable arsenate esters that spontaneously hydrolyze and thereby short-circuit energy-yielding bioenergetic processes. In other cases, the pentavalent arsenicals may exert toxic effects after being reduced in vivo to trivalent forms. 

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. 

TThe catabolic production of ammonia poses a serious biochemical problem, because ammonia is very toxic. The molecular basis for this toxicity is not entirely understood. The terminal stages of ammonia intoxication in humans are characterized by onset of a comatose state accompanied by cerebral edema (an increase in the brain s water content) and increased cranial pressure, so research and speculation on ammonia toxicity have focused on this tissue. Speculation centers on a potential depletion of ATP in brain cells. 

It IS proposed that the term "heavy metals" be abandoned in favor of a classifeation which separates metals. .. according to their binding preferences. . . related lo atomic properties.. . A review of the roles of metal ions in biological sysicms demonstrates the potential of the proposed classification for interpreting Ihe biochemical basis for metal-ion toxicity.. . . ... 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

Question What is the biochemical and pharmacological basis for the observation that coadministration of epinephrine with procaine leads to an increase in the duration of action as well as a decrease in systemic toxicity of procaine ... 

The biochemical basis for bleomycin cytotoxicity and pulmonary toxicity may involve the generation of reactive oxygen species by a complex of bleomycin with iron. This complex has been shown to catalyse the formation of 02 and HO capable of causing DNA strand excision (Sausville et al. 1978) and lipid peroxidation (Kameda et al. 1979). 

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. 

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