Toxicological significance of oxidation

Toxicological Significance of Oxidation and Rearrangement Reactions of iS -Chloroallyl Thio-and Dithiocarbamate Herbicides... 

A 32% increase in liver weights, along with a 187% increase in peroxisomal beta-oxidation activity, was noted in rats exposed to 1,000 mg/kg/day MIL-H-5606 for 26 days (Mattie et al. 1993). The toxicological significance of the changes in peroxisomal enzyme activities is unclear. 

This review considers the -chloroallyl thio- and dithiocar-bamate herbicides with particular emphasis on the toxicological significance of their oxidation and rearrangement reactions. 

Any high-temperature combustion process in air initially generates nitric oxide and some nitrogen dioxide, but the former becomes rapidly oxidized to the latter. Combustion processes may produce other forms of nitrogen-containing compounds, such as nitrous and nitric acid vapors however, the toxicological significance of these is not certain. 

Sulfhemoglobin is most likely a mixture of oxidized and partially denatured hemoglobins. The toxicologic significance of sulfhemoglobin is not clear, except it appears to be... 

Trichloroethylene oxide (trichlorooxirane, 10.89, Fig. 10.22) has received particular attention due to its toxicological significance and the widespread use of its parent compound trichloroethylene (10.87) [153] [155]. Chloral... 

Two further compounds are briefly discussed here. Tetrachloroethylene administered to animals yielded 2,2,2-trichloroacetic acid (10.95, Fig. 10.23) as the only chlorinated metabolite [13]. These findings provided the first evidence that tetrachloroethylene is oxidized by cytochrome P450 to its epoxide (10.94), which rearranges by Cl migration to 2,2,2-trichloroacetyl chloride (Fig. 10.23). The latter hydrolyzes to 2,2,2-trichloroacetic acid (10.95), but also acylates tissue proteins, a reaction of unclear toxicological significance. In vitro investigations of tetrachloroethylene oxide (2,2,3,3-tetrachlo-rooxirane, 10.94) further showed that it hydrolyzes to the vicinal diol (10.96... 

Parathion and Paraoxon. Again, this represents a reaction (the sulfur oxidation of a thiophosphate pesticide) that is familiar to most in the pesticide area. Unlike heptachlor epoxide, paraoxon is not a stable compound and its actual presence in a poisoned animal was very difficult to demonstrate. The oxons of other organo-phosphorothioates are not so elusive. In any event, the paraoxon metabolite is an excellent example of where an understanding of metabolic processes and their potential toxicological significance alerted scientists to the likelihood that such a metabolite existed. Many years of work with similar compounds had established that the insecticidal thiophosphates required oxidation to the P=0 form in order to inhibit the neurotrasmitter acetylcholinesterase, the biochemical basis of their toxic action. Paraoxon was eventually isolated in vivo and now consideration of the oxon is a vital part of the overall risk assessment of this group of pesticides. 

We examine here a number of reaction pathways for nitric oxide, with the emphasis on assessing their biological relevance. To date, the fastest reaction for nitric oxide with clear toxicological significance is that with superoxide to produce ONOO" (Huie and Padmaja, 1993). Thus, the chemistry and reactivity of ONOO" are discussed at length. In addition, the interaction between ONOO" and nitric oxide is examined with respect to its effects on nitric oxide half-life as well as effects on peroxynitrite reactivity toward phenol. Reaction mechanisms are proposed to account for the nitrated, hydroxylated, and nitrosated phenolic products seen. 

A number of reactions of reduction have been demonstrated in the metabolism of xenobiotics. From a quantitative viewpoint, they are less important than oxidations since our organism is mostly an aerobic one. From a qualitative point of view, however, reactions of reduction may be of great pharmacological or toxicological significance when they generate active metabolites or toxic metabolic intermediates. 

Af-oxides back to the amine (see Fig. 31.25). The same is true for aromatic nitro compounds, aromatic nitroso compounds and hydroxylamines, and imines and oximes, which can ultimately be reduced to primary amines. Azo and azoxy compounds can be reduced to hydrazines. An important pathway of hydrazines is their reductive cleavage to primary amines. A toxicologically significant pathway thus exists for the reduction of some aromatic azo compounds to potentially toxic prUnary aromatic amines. 

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