Lipophilic toxicants, metabolic

Some chemicals that strongly bind to biological receptors (ligands) can produce toxicity directly. However, most toxic chemicals are not intrinsically reactive and must be metabolized to reactive intermediates that often covalently bind to macromolecules (DNA, proteins, etc.), and, if present at a sufficient level, lead to toxicity. Metabolism generally serves to make lipophilic compounds more hydrophilic in order to facilitate excretion through the liver and into the bile for excretion into the feces or through the kidneys and into the urine. This process generally... 

Metabolic transformation of lipophilic toxicants including pesticide and plant allelochemicals to excretable products usually proceeds by a series of enzymatic events to ultimately detoxify the chemical. Many of the initial reactions can generate intermediates... 

The DDT group insecticides are environmentally persistent because they have very low water solubility and vapor pressure and moderate stability to sunlight. For example, the water solubility of DDT is less than 2 ppb (parts per billion), and its vapor pressure is 1.5 x 10 7 mm Hg at 20°C. These compounds are also highly lipophilic and metabolically stable. As a result, they are persistent biologically and tend to bioaccumulate. The toxicity of this group is low... 

Toxicants that are ingested generally are absorbed through the small intestine walls and are transported to the liver. The liver is the main site of toxicant metabolism and is where some poisonous substances are converted to less toxic forms more readily eliminated from the body whereas other substances are converted to toxic species. Toxic species are distributed around the body by the blood and lymph system, which can lead to systemic poisoning at sites remote from the entry of the substance into the body. Bone and adipose tissue (fat) are major sites of storage of toxicants. Bone accumulates heavy metals including lead and some radioactive materials, especially strontium-90, which biochemically behaves like calcium. Radioactive iodine accumulates in the thyroid and can cause thyroid cancer. Lipophilic toxicants, such as polychlorinated biphenyls (PCBs), that are poorly soluble in water tend to accumulate in adipose tissue. 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

The attraction of lipophilicity in medicinal chemistry is mainly due to Corwin Hansch s work and thus it is traditionally related to pharmacodynamic processes. However, following the evolution of the drug discovery process, lipophilicity is today one of the most relevant properties also in absorption, distribuhon, metabolism, excretion and toxicity (ADMET) prediction, and thus in drug profiling (details are given in Chapter 2). 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Among chemical-physics properties, lipophilicity is certainly a key parameter to understand and predict absorption, distribution, metabolism, excretion, and toxicity (ADMET) of NCE furthermore, it contributes to model ligand-target interactions underlying the pharmacodynamic phase [15],... 

In mammals the cytochrome P-U50 mediated monooxygenase or mixed function oxidase system involved in the elimination of lipophilic environmental contaminants and other foreign compounds, has been implicated in the carcinogen activation process. There are several distinct variants of cytochrome P-U50 in mammalian tissues and there may be more than one form of this ubiquitous cytochrome also in fish. The significance of this lies in the fact that different forms of cytochrome P-U50 result in different metabolite patterns, which in turn may reflect on the carcinogenicity or toxicity of compounds being metabolized. 

Chlorinated micropoUutants are harmful for man and environment due to their toxicity, persistence, and bioaccumulation. Persistent compounds are very stable and difficult to get metabolized and mineralized by biological and chemical processes in the environment, and as a result, they have become ubiquitous in water, sediments, and the atmosphere bioaccumulation is the result of the lipophilicity of these compounds. Polychlorinated dibenzodioxins and -furans (PCDD/F) are not produced purposely like many of other chlorinated technical products, such as chlorinated biocides DDT, lindane, and toxaphene. The production and use of persistent organic pollutants (POPs), the dirty dozen has now been banned worldwide by the Stockholm protocol. It should be mentioned that about 3000 halogenated products have now been isolated as natural products in plants, microorganisms, and animals," but the total amount of these products is much smaller compared to xenobiotics. 

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