Toxicity metabolic differences

Effects of Metaboiism on Toxicity. Metabolism plays an important role in the toxicity of trichloroethylene because many of its metabolites are themselves toxic. Many differences among species in their responses to trichloroethylene exposure may be attributed to differences in the rates at which they metabolize the parent compound (Dekant et al. 1986b Prout et al. 1985). 

Metabolic differences betw een humans and other animals may account for some of the interspecies differences in specific organ toxicity of trichloroethylene (see below). Among humans, sexual differences due mainly to the effects of body fat content on trichloroethylene absorption are expected based on PBPK modeling (see Section 2.3.5). 

The liver is an organ that shows variable effects from trichloroethylene among species, and this can probably be attributed to interspecies differences in metabolism (see Section 2.4.2.1). Specifically, the apparent difference in susceptibility to trichloroethylene-induced hepatocellular carcinoma between humans and rodents may be due to metabolic differences (see Section 2.4.2.3). Kidney effects are also variable among species. Humans and mice are less sensitive than rats. In rats exposed chronically to trichloroethylene, toxic nephrosis characterized as cytomegaly has been reported (NTP 1988). The kidney effects in rats do not seem to be related to an increase in alpha-2 -globulin (Goldsworthy et al. 1988). Effects on the nervous system appear to be widespread among species, presumably due to interactions between trichloroethylene and neuronal membranes. 

In toxicity studies, acute toxicity tests are usually carried out in the rat, mouse, cat, and dog. Subacute toxicity studies for IM products are performed by giving SC injections to rats and IM injections to dogs. In IV studies the rat tail vein or a front leg is used. Deliberate overdosing usually washes out metabolism differences between species. In dogs it is common to give an IV dose five times that intended for humans. In rats this is increased to 10 times. 

Lucci A, Giuliano AE, Han TY, Dinur T, Liu YY, Senchenkov A, Cabot MC (1999) Ceramide toxicity and metabolism differ in wild-type and multidrug-resistant cancer cells. Int J Oncol 15(3) 535-540... 

As with absorption and distribution, the nature and rate of metabolic transformations vary among individuals and different animal species. Metabolism differences can be extreme, and may be the most important factor accounting for differences in response to chemical toxicity among animal species and individuals within a species. The more understanding toxicologists acquire of metabolism, the more they shall understand the range of responses exhibited by different species and individuals, and the better they shall be able to evaluate toxic risks to humans. 

Metabolic differences also account for the great species variability in methyl alcohol toxicity with humans and nonhuman primates being uniquely sensitive. (A relatively poor ability to metabolize the methanol-metabolized formate in these species leads to increased blood formate levels and subsequent metabolic acidosis and neuronal toxicity.)... 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

In some cases, species differences in toxicity are due to more than one metabolic difference. For example, research on the fungal toxin aflatoxin B1 indicates that humans are particularly susceptible, more so than rodents, with rats being more susceptible than mice. Interestingly, cynomologous monkeys are also relatively insensitive probably due to the lack of constitutive CYP1A2. 

The onset of symptoms depends on the particular organophosphorus compound, but is usually relatively rapid, occurring within a few minutes to a few hours, and the symptoms may last for several days. This depends on the metabolism and distribution of the particular compound and factors such as lipophilicity. Some of the organophosphorus insecticides such as malathion, for example (chap. 5, Fig. 12), are metabolized in mammals mainly by hydrolysis to polar metabolites, which are readily excreted, whereas in the insect, oxidative metabolism occurs, which produces the cholinesterase inhibitor. Metabolic differences between the target and nontarget species are exploited to maximize the selective toxicity. Consequently, malathion has a low toxicity to mammals such as the rat in which the LD50 is about 10 g kg-1. 

The above paragraphs summarize some of the studies in this area, and indicate that in preparing potentially useful biologically active agents of all classes, thiophene and ben-zothiophene rings may replace benzene, naphthalene or indole rings to produce active compounds which may be less toxic, have different physiological disposition and/or different modes of metabolism or detoxification, and thus impart desirable properties. 

Because exogenous chemicals can be inducers and/or inhibitors of the xenobiotic-metabolizing enzymes of which they are substrates such chemicals may interact to bring about toxic sequelae different from those that might be expected from any of them administered alone. 

Calcium and magnesium are very abundant in soils, and soils deficient in Ca are rare, calcium status is maintained when lime is added to correct acidity. Plant cells contain relatively large concentrations of Ca, but most of it is bound in the cell-wall as the pectate (about 60%) or sequestered in different organelles (Clarkson, 1984). Ca affects the permeability of the cytoplasmic membrane and its deficiency leads to malformation of the growing parts of the plant. Hewitt and Smith (1975) have discussed the early experiments on the morphological effects of Ca deficiency. Calcium is often found in combination with organic acids, for example oxalic acid, a soluble, toxic metabolic by-product is converted to insoluble calcium oxalate. 

This principle is based on numerous observations that species, strains, and even lit-termates (or siblings) exhibit differential susceptibility to the same developmental toxicant. These differences are attributed to variations in biochemical and morphological attributes that are genetically determined. Disparities in which a toxicant is absorbed, metabolized, or eliminated by both the mother and conceptus, as well as its ability to interact with certain cell types or components, are thought to underlie the variations in susceptibility. 

The toxicity and bioavailability can be varied by conjugation to form new derivatives such as glu-curonides that are metabolized differently than the parent compound. An example is a glucuronide derivative of the aminophenol amide of dX -trans retinoic acid, fenretinamide (A-(4-hydroxyphenyl)-retinamide, 4-HPR) (117). 

Similarity/differences between enantiomers Pharmacodynamics (pharmacology and toxicity) Metabolic disposition... 

Salicylamide reportedly exerts a moderately quicker and deeper analgesic effect than aspirin. Long-term studies on rats revealed no untoward symptomatic or physiological reactions. Its metabolism differs from that of other salicylic compounds, and it is not hydrolyzed to salicylic acid." Its analge.sic and antipyretic activity is probably no greater than that of aspirin, and possibly less. It can be used in place of salicylates, however, and is particularly useful for patients with a demonstrated sensitivity to salicylates. It is excreted much more rapidly than other salicylates, which probably accounts for its lower toxicity and. thus, does not permit high blixHl levels. 

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