Protoxicants

Activation of protoxicants to reactive, and potentially toxic, metabolites... 

Having examined the routes by which toxicants enter the body, it is now appropriate to consider what happens to them in the body and what their effects are. The action of a toxic substance can be divided into two major phases, as illustrated in Figure 6.10. The kinetic phase involves absorption, metabolism, temporary storage, distribution, and, to a certain extent, excretion of the toxicant or its precursor compound, called the protoxicant. In the most favorable scenario for an organism, a toxicant is absorbed, detoxified by metabolic processes, and excreted with no harm resulting. In... 

What is a protoxicant What may happen to a protoxicant in the kinetic phase ... 

This compound is a protoxicant that readily crosses the blood-brain barrier, where it is acted on by the monoamine oxidase enzyme system to produce a positively charged neurotoxic species that cannot readily cross the blood-brain barrier to leave the brain. The result has been described as selective neuronal death of the dopaminergic neurons in the zona compacta of the substantia nigra. 3 The symptoms of this disorder are very similar to Parkinson s disease, one of several common and devastating neurodegenerative diseases. 

Electrophiles not only complex with macromolecular nucleophilic sites, but also complex with those of small molecules. The most important of these is the -SH group of GSH. Conjugation of electrophiles with GSH is an important detoxication reaction catalyzed by GSH transferases (see Chapter 12). Although GSH concentration in hepatocytes is high relative to other tissues (4-8mM), depletion of GSH can occur upon acute exposure to protoxicants whose electrophilic metabolites... 

Concentration of chemicals in intraluminal fluid Reabsorption and/or secretion of chemicals through tubular cells Biotransformtion of protoxicants to reactive intermediates... 

Fourth, certain segments of the nephron have a capacity for metabolic bioactivation. For example, the proximal and distal tubules contain isozymes of the cytochrome P450 monooxygenase system that may mediate intrarenal bioactivation of several protoxicants. Additionally, prostaglandin synthetase activity in medullary and papillary interstitial cells may be involved in cooxidation of protoxicants, resulting in selective papillary injury. 

Barber, D., Correll, L., Ehrich, M. (1999). Comparative effectiveness of organophosphorus protoxicant activating systems in neuroblastoma cells and brain homogenates. J. Toxicol. Environ. Health, Part A 57 63-74. 

S-containing phosphorothionate compounds. It is generally recognized that these phosphorothionate compounds are not active toxicants but rather protoxicants. Oxidation, which results in exchange of the doubly bonded sulfur for a doubly bonded oxygen, is necessary for conversion of the protoxicant phosphorothionate compounds to active neurotoxicants. 

Knowles and Milner, 2000). Furthermore, these compounds are thought to be involved in the inhibition of certain cytochrome P-450 enzyme-dependent bioactivations of procarcinogens and protoxicants (Brady et al., 1991), as well as to increase levels of glutathione-S-transferase (GST), an enzyme of particular importance in the detoxification of xenobiotics in the body (Wilce and Parker, 1994). Most recently, the ability of various plants and plant extracts to influence apoptosis, or programmed cell death, in cancerous cells in an attempt to arrest their proliferation, has been the topic of much research. Allicin has been shown to induce apoptosis in a variety of cell lines, including human hepatocellular carcinoma cells (KIM-1) and human lymphoid leukemia (MOLT-4B) cells (Thatte et al., 2000). 

In the kinetic phase a toxicant or the metaboUc precursor of a toxic species (protoxicant) may undergo absorption, metabolism, temporary storage, distribution, and excretion (Figure 11). 

Figure 10. Physiological pathways of toxicants in the body Manahan, 1994). Toxicant Protoxicant...

Figure 11. Physiological processes involving toxicants or protoxicants in the kinetic phase.

Although many toxic snbstances are foreign to living systems and are called xenobiotic substances, others are produced by organisms. Many toxicants, especially xenobiotics, have an affinity for lipids, meaning that they undergo bioaccumulation in the fat tissne of animals and cross the lipid cell membranes readily. Probably, most substances classified as toxic require activation by biochemical processes to have any toxic effects and are properly called protoxicants. 

FIGURE 2.13 Toxicology is the science dealing with various aspects of the effects of poisonous substances on organisms. Toxicological chemistry relates the chemical nature of toxicants and protoxicants to their toxic effects on organisms. 

An important aspect of toxicological chemistry is that of the reactions that toxicants and protoxicants undergo in a living system before they even have any toxic effects. These are divided into Phase I and Phase II reactions. 

Typically, lipid-soIuble toxicants and protoxicants are converted by Phase I reactions to species that are more polar and water-soluble and more easily eliminated from the body through urine (Figure 2.14) compared to the species from which they are made. This usually occurs through attachment of an -OH group. A Phase I reaction is generally catalyzed by the cytochrome P-450 enzyme system associated with cellular endoplasmic reticulum, which occurs most abundantly in the liver of vertebrates. A typical Phase I reaction is the production of phenol from benzene ... 

In an organism, toxicants and protoxicants are ingested, undergo metabolic processes (Phase I and Phase II reactions), bind with biochemical species such as blood hemoglobin or DNA, and are excreted. Normally, through binding with endogenous biomolecules, toxicants exert some sort of toxic effect. These various processes are conveniently divided between the kinetic phase and the dynamic phase. 

FIGURE 2.16 Illustration of the kinetic phase of metabolism for toxicants and protoxicants. In this phase, a protoxicant may be metabolically converted to a toxic species. A toxicant may be detoxified and excreted without doing harm, remain unchanged as an active parent compound that may have a toxic effect, or converted to another active metabolite that is potentially toxic. 

Exposure to vinyl chloride is known to cause a specific kind of liver cancer in humans. After doing some Internet research on the subject, explain the statenentthat vinyl chloride is a xenobiotic compound and a protoxicant. 

In the kinetic phase, a toxicant or its metabolic precursor (protoxicant) may undergo absorption, metabolism, temporary storage, distribution, and excretion, as illustrated in Figure 23.9. A toxicant that is absorbed may be passed through the kinetic phase unchanged as an active parent compound, metabolized to a detoxified metabolite that is excreted, or converted to a toxic active metabolite. These processes occur through Phase I and Phase II reactions discussed above. 

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