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toxicant is free or available to diffuse across the cell membranes. The toxicant-protein binding reaction is reversible and obeys the laws of mass action:
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k1 Toxicant + Protein Toxicant-Protein (free) k2 (bound)
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Usually the ratio of unbound plasma concentration (Cu ) of the toxicant to total toxicant concentration in plasma (C) is the fraction of drug unbound, fu , that is, fu = Cu . C
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The constants k1 and k2 are the speci c rate constants for association and dissociation, respectively. The association constant Ka will be the ratio k1 /k2 , and conversely, the dissociation constant, Kd will be k2 /k1 . The constants and parameters are often used to describe and, more important, to compare the relative af nity of xenobiotics for plasma proteins. The are many circulating proteins, but those involved in binding xenobiotics include albumin, 1 -acid glycoprotein, lipoproteins, and globulins. Because many toxicants are lipophilic, they are likely to bind to plasma - and -lipoproteins. There are mainly three classes of lipoproteins, namely high-density lipoprotein (HDL), lowdensity lipoprotein (LDL), and very low density lipoprotein (VLDL). Iron and copper are known to interact strongly with the metal-binding globulins transferin and ceruloplasmin, respectively. Acidic drugs bind primarily to albumin, and basic drugs are bound primarily to 1 -acid glycoprotein and -globulin. Albumin makes up 50% of total plasma proteins, and it reacts with a wide variety of drugs and toxicants. The 1 -acid glycoprotein does not have as many binding sites as albumin, but it has one high-af nity binding site. The amount of toxicant drug that is bound depends on free drug concentration, and its af nity for the binding sites, and protein concentration. Plasma protein binding is nonselective, and therefore toxicants and drugs with similar physicochemical characteristics can compete with each other and endogenous substances for binding sites. Binding to these proteins does not necessarily prevent the toxicant from reaching the site of action, but it slows the rate at which the toxicant reaches a concentration suf cient to produce a toxicological effect. Again, this is related to what fraction of the toxicant is free or unbound (fu ). Toxicants complex with proteins by various mechanisms. Covalent binding may have a pronounced effect on an organism due to the modi cation of an essential molecule, but such binding is usually a very minor portion of the total dose. Because covalently bound molecules dissociate very slowly, if at all, they are not considered further in this discussion. However, we should recognize that these interactions are often associated with carcinogenic metabolites. Noncovalent binding is of primary importance to distribution because the toxicant or ligand can dissociate more readily than it can in covalent binding. In rare cases the noncovalent bond may be so stable that the toxicant remains bound for weeks or months, and for all practical purposes, the bond is equivalent to a covalent one. Types of interactions that lead to noncovalent binding under the proper physiological conditions include ionic binding, hydrogen bonding, van der Waals forces, and hydrophobic interactions. There are, however, some transition metals that have high association constants and dissociation is slow.
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We know more about ligand-protein interactions today because of the numerous protein binding studies performed with drugs. The major difference between drugs and most toxicants is the frequent ionizability and high water solubility of drugs as compared with the non-ionizability and high lipid solubility of many toxicants. Thus experience with drugs forms an important background, but one that may not always be relevant to other potentially toxic compounds. Variation in chemical and physical features can affect binding to plasma constituents. Table 6.4 shows the results of binding studies with a group of insecticides with greatly differing water and lipid solubilities. The af nity for albumin and lipoproteins is inversely related to water solubility, although the relation may be imperfect. Chlorinated hydrocarbons bind strongly to albumin but even more strongly to lipoproteins. Strongly lipophilic organophosphates bind to both protein groups, whereas more watersoluble compounds bind primarily to albumin. The most water-soluble compounds appear to be transported primarily in the aqueous phase. Chlordecone (Kepone) has partitioning characteristics that cause it to bind in the liver, whereas DDE, the metabolite of DDT, partitions into fatty depots. Thus the toxicological implications for these two compounds may be quite different. Although highly speci c (high-af nity, low-capacity) binding is more common with drugs, examples of speci c binding for toxicants seem less common. It seems probable that low-af nity, high-capacity binding describes most cases of toxicant binding. The number of binding sites can only be estimated, often with considerable error, because of the nonspeci c nature of the interaction. The number of ligand or toxicant molecules bound per protein molecule, and the maximum number of binding sites, n, de ne the de nitive capacity of the protein. Another consideration is the binding af nity Kbinding (or 1/Kdiss ). If the protein has only one binding site for the toxicant, a single value, Kbinding , describes the strength of the interaction. Usually more than one binding site is present, each site having its intrinsic binding constant, k1 , k2 , . . . , kn . Rarely does one nd a case where k1 = k2 = . . . = kn , where a single value would describe the af nity
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Table 6.4 Relative Distribution of Insecticides into Albumin and Lipoproteins Percent Distribution of Bound Insecticide Insecticide DDT Deildrin Lindane Parathion Diazinon Carbaryl Carbofuran Aldicarb Nicotine Percent Bound 99.9 99.9 98.0 98.7 96.6 97.4 73.6 30.0 25.0 Albumin 35 12 37 67 55 99 97 94 94 LOL 35 50 38 21 31 <1 1 2 2 HDL 30 38 25 12 14 <1 2 4 4
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Source: Adapted from B. P. Maliwal and F. E. Guthrie, Chem Biol Interact 35:177 188, 1981. Note: LOL, low-density lipoprotein; HOL, high-density lipoprotein.
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