Metabohc activity

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

In 1956 selenium was identified (123) as an essential micronutrient iu nutrition. In conjunction with vitamin E, selenium is effective iu the prevention of muscular dystrophy iu animals. Sodium selenite is adrninistered to prevent exudative diathesis iu chicks, a condition iu which fluid leaks out of the tissues white muscle disease iu sheep and infertility iu ewes (see Eeed ADDITIVES). Selenium lessens the iacidence of pneumonia iu lambs and of premature, weak, and stillborn calves controls hepatosis dietetica iu pigs and decreases muscular inflammation iu horses. White muscle disease, widespread iu sheep and cattle of the selenium-deficient areas of New Zealand and the United States, is insignificant iu high selenium soil areas. The supplementation of animal feeds with selenium was approved by the U.S. EDA iu 1974 (see Eeed additives). Much of selenium s metaboHc activity results from its involvement iu the selenoproteia enzyme, glutathione peroxidase. 

The guarded hot-plate method can be modified to perform dry and wet heat transfer testing (sweating skin model). Some plates contain simulated sweat glands and use a pumping mechanism to deUver water to the plate surface. Thermal comfort properties that can be deterrnined from this test are do, permeabihty index (/ ), and comfort limits. PermeabiUty index indicates moisture—heat permeabiUty through the fabric on a scale of 0 (completely impermeable) to 1 (completely permeable). This parameter indicates the effect of skin moisture on heat loss. Comfort limits are the predicted metaboHc activity levels that may be sustained while maintaining body thermal comfort in the test environment. 

The metaboHsm of a material may result in the formation of a transformation product of lower intrinsic toxicity than the parent molecule ie, a process of detoxification has occurred. In other cases, the end result is a metaboHte, or metaboHtes, of intrinsically greater toxicity than the parent molecule, ie, metaboHc activation has occurred. Some examples of detoxification and metaboHc-activation processes are given in Table 2. 

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

Fig. 3. Schematic representation showing the anatomical basis for differences in the quantitative supply of absorbed material to the Hver. By swallowing (oral route), the main fraction of the absorbed dose is transported direcdy to the Hver. FoUowing inhalation or dermal exposure, the material passes to the pulmonary circulation and thence to the systemic circulation, from which only a portion passes to the Hver. This discrepancy in the amount of absorbed material passing to the Hver may account for differences in toxicity of a material by inhalation and skin contact, compared with its toxicity by swallowing, if metaboHsm of the material in the Hver is significant in its detoxification or metaboHc activation.

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Sodium chlorite is not Hsted by the USEPA or any regulatory authority as a carcinogen. Studies conducted ia mice and rats did not show an increase in tumors in animals exposed to sodium chlorite in thek drinking water. Sodium chlorite has been found to have mutagenic activity in some in vitro test systems such as the Ames Salmonella reverse mutation assay without the presence of metaboHc activators. The significance of these test results in regard to human health is not clear because of the oxidizing effects of the chlorite ion (149). 

Benzyl chloride induced a positive mutagenic response ia the Ames Assay ia strain TA 100 with and without rat Hver S-9 metaboHc activation. 

Biological Corrosion The metabohc activity of microorganisms can either directly or indirectly cause deterioration of a metal by corrosion processes. Such activity can (1) produce a corrosive environment, (2) create electrolytic-concentration cells on the metal surface, (3) alter the resistance of surface films, (4) have an influence on the rate of anodic or cathodic reaction, and (5) alter the environment composition. 

Hexachlorophane inhibits the electron transport chain in bacteria and thus will inhibit all metabohc activities in aerobic bacteria. 

Hammer, R. P. Herkenham, M. (1983). Altered metabohc activity in the cerebral cortex of rats exposed to ketamine. J. Comp. Neurol. 220, 396-404. 

J. F. Newton, D. A. Pasino, J. B. Hook, Acetaminophen Nephrotoxicity in the Rat Quantitation of Renal Metabohc Activation in vivo, Toxicol. Appl. Pharmacol. 1985, 78, 39-46. 

Tests for mutation in Aspergillus nidulans are performed in hquid suspension. Conidia are exposed to the test substance both with and without metabohc activation and plated on selective medium to determine changes in colonial morphology or nutritional requirements. At the end of a suitable incubation period, mutant colonies are counted and compared to the number of spontaneous mutants in an untreated control culture. Simultaneous determination of survival... 

Tamaki N, Ohtani H, Yamashita K, Magata Y, Yonekura Y, Nohara R et al. Metabohc activity in the areas of new fill-in after thallium-201 reinjection comparison with positron emission tomography using fluor-ine-18-deoxyglucose. J Nucl Med 1991 32 673-678... 

D Hondt S., Rutherford S., and Spivack A. J. (2002) Metabohc activity of subsurface life in deep-sea sediments. Science 295, 2067-2070. 

In a series of thyrocardiac patients, of those dying primarily from thyrotoxicosis more than 21% did so within 3 weeks of I treatment (8), presumably reflecting too sudden a change in metabohc activity for patients with existing cardiac comphcations. 

Sparteine has been used as a marker of the metabohc activity of CYP2D6 (1). Pharmacokinetic studies have shown that its metabolic oxidation exhibits genetic polymorphism and that about 6-9% of the Caucasian population are poor metabohzers. Quinidine, haloperidol, and moclobemide are all potent inhibitors of the oxidative metabohsm of sparteine (2). 

Within metabohcally active and vitamin K using tissue, especially liver, a microsomal vitamin K cycle exists (Figure 30-7). The vitamin (quinone) is normafty reduced by a thiol-sensitive flavoprotein system to the hydroquinone, which then can couple to the oxygen- and carbon dioxideusing y-carboxyiation of glutamyl residues in specific pro-... 

Infants and children older than one year are considered to be very efficient metabohzers of drugs and may actually require larger doses than those predicted by weight adjustment of adult doses or shorter dosing intervals (35). On the basis of metabohc activity, sustained-release formulations would appear to be ideal for children of 1 to 10 years if bioavailability issues would prove not to be problematic. The ability to clear drugs in critically iU children may be severely compromised therefore, dosing in this subgroup of patients requires careful titration (36). 

Kalgutkar, A. S., Soglia, J. R. Minimizing the potential for metabohc activation in drug discovery. Expert Opin. Drug Metab. Toxicol. 2005, 7,91-141. 

Equation (2) expresses the metaboHc activity of the microorganism, measured in the presence of the particular solvent, relative to the positive control, that is, when the metabohsm of the microorganism is uninhibited. Both of these values are corrected for any changes in the biomass concentration that might have occurred due to stress or any other process (es), with exception of the utilization of carbon and energy source. This is done by subtracting Xiegative control- After aU the Z values are calculated, these are plotted as a function of the respective log P values. This is demonstrated for a hypothetical MO in Fig. 8.2. 

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