Toxic metabolic products systemic action

In an animal, a xenobiotic substance may be bound reversibly to a plasma protein in an inactivated form. A polar xenobiotic substance, or a polar metabolic product, may be excreted from the body in solution in urine. Nonpolar substances delivered to the intestinal tract in bile are eliminated with feces. Volatile nonpolar substances such as carbon monoxide tend to leave the body via the pulmonary system. The ingestion, biotransformation, action on receptor sites, and excretion of a toxic substance may involve complex interactions of biochemical and physiological parameters. The study of these parameters within a framework of metabolism and kinetics is called toxicometrics. 

Nitroprusside [nye troe PRUSS ide] is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. It is capable of reducing blood pressure in all patients, regardless of the cause of hypertension. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. [Note Because nitroprusside also acts on the veins, it can reduce cardiac preload.] Nitroprusside is metabolized rapidly (t1/2 of minutes) and requires continuous infusion to maintain its hypotensive action. Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production, although cyanide toxicity is rare and can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys (Figure 19.14). [Note Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.]... 

The powerful action of some natural products on the central nervous system may suggest their potential value in insect control. If their mammalian toxicity can be reduced by structural modification they may be useful insecticides. Cartap, a rice insecticide, is a bisthiocarbamate. Its structure was based on that of the natural product, nereistoxln, a neurotoxin isolated from shellfish, and it is likely that an in vivo metabolic conversion of cartap to nereistoxln or related compound is responsible for its activity (11). 

For example, the induction of metabolizing enzymes by a chemical can greatly modify its PK and that of other substances, which is the subject of metabolic interactions [59], Intestinal barrier alterations due to intestinal toxicity can also affect PK [3]. Toxicity-induced retro-action mechanisms can also increase volumes of distribution The interaction of a chemical with aromatase can lead to a decrease in estradiol production and hence a decrease in FSH secretion, followed by a decrease in follicular growth and a reduction of the ovary volume [56], This should have implications for the design of in vitro assay systems. Integrated systems, such as those coupling metabolism and effect observations in human on chip micro-devices [5], offer a way to model experimentally the PK/PD continuum. 

The action of toxic doses of atropine is observed on the central nervous system. There is a functional alteration of the brain as well as lower regions of the nervous system. There is neither an increase nor decrease of the reflexes except in the last stages corresponding to the coma, anesthesia, and profound depression of the brain. The bulbar respiratory center is stimulated, the respiration being increased in rate and amplitude during the stage of central stimulation. Cushny (120) stated that it is not known whether there is a direct action on the center or an indirect effect due to the products of metabolism such as carbon dioxide. But even small doses which cause no general excitation provoke a respiratory stimulation which makes it probable that there exists a direct action on the bulbar respiratory center (119). 

Adequate iodine intake is indispensable to the production of thyroid hormone (TH), which is essential for growth, development and cell differentiation. Iodine excess, as well as iodine deficiency, has adverse effects on health. One of the aims of the present review is to summarize the previous evidence and present the major advances in our knowledge of developmental toxic effects induced by excess iodine in animals and humans. Fetal and maternal thyroid systems interact mainly by means of the placenta. When a mother is exposed to excess iodine, alterations in maternal-fetal TH metabolism occur. Another aim of this review is to discuss the pathway of maternal-fetal TH metabolism influenced by excess iodine. Finally, the present review provides new insights into the molecular mechanism of TH action in skeletal development and highlights the potential regulation of the developmental genes, Hox genes (especially HoxcS), by TH in skeletal development. 

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