Organotropy

Organotropy, affinity for organs; a term introduced by Ehrlich. The doctrine of O. is closely connected with the doctrine of parasitotropy and chemotherapy. A red thread through all of Ehrlich's work on the latter question is the idea that the relationship between the cells of the organism and any chemical substance is in close dependence on the degree of affinity between them. As early as in experiments with vital staining, Ehrlich was able to ascertain that injected dyes do not spread diffusely and uniformly throughout all tissues of the organism, but are fixed only on certain elements: thus, methylene blue under such conditions stains the finest branches of the nerve axons; Neutralred stains the granules of the body's cells; methylene blue, Bismarck brown, Neutralred and still some other dyes stain the brain vital. Consequently, depending on their chemical structure, dyes in some cases exhibit 'tropism' for the nervous system, being neurotropic, in others they stain fat and thus prove to be lipotropic, etc. Ehrlich uses these observations made on dyes to explain the selective action of poisons and generally various pharmacological substances on different parts of the organism, and consequently also why some substances act on brain centers, others on the endings of the peripheral nervous system, third on the liver, etc. The intimate mechanism of such tropism Ehrlich tried to uncover, proceeding from his basic views on the physiology of cell nutrition and on immunity, more precisely-on the question of the relationship between toxin and antitoxin, as well as generally between antigens and antibodies. Every cell, in Ehrlich's view, in order to assimilate various nutrients must possess certain groupings of a chemical nature, called by him nutritive receptors or (more generally) simply receptors. Proof of the existence of the latter Ehrlich sees in the fact of antibody formation, which he interprets in the aspect of his so-called side-chain theory. But antigens are substances of relatively complex nature. It is more difficult to decide whether similar functional groups exist for the assimilation of other, less complex substances. With respect to the simplest function of the cell- the binding of oxygen- he considers this question partly resolved, since in the hemoglobin molecule, in the case of loose binding, on the one hand, of oxygen, on the other- of carbon monoxide and hydrocyanic acid, the mediating agent is organically bound iron. Therefore, he admitted the existence in the protoplasm of erythrocytes of certain groupings, which, possessing maximum affinity for iron, form with it a complex compound with characteristic functional properties (the so-called 'ferroreceptors'). In a similar way, he considered it possible to imagine the presence in the blue coloring matter, which determines respiration in crabs, of 'cuproreceptors', in other animals- 'manganoreceptors'. A similar explanation, in his opinion, also admits the fact of the localization of iodine in the thyroid gland, as well as the grouping of iodine in certain aromatic side chains. The latter leads to the difficult question of whether there are grounds for assuming the existence of similar preformed 'chemoreceptors', or 'chemocenters', for a number of drugs; in other words- to the question 'de sedibus et causis pharmakorum'. Ehrlich answers this question affirmatively, based on his observations on trypanosomes. The latter, as simplest, unicellular organisms, presented much more favorable material for study than complex multicellular organisms. The study of parasitotropy thus led to the study of O. As early as Koch had attempted to treat anthrax with corrosive sublimate. However, it turned out that anthrax bacilli, having entered the organism, do not die even when the total amount of introduced sublimate exceeds the titer which in vitro already produces a marked microbicidal action. Obviously, sublimate is rapidly bound by organs and tissues. Similarly, according to Hata's data, methylene blue kills syphilis spirochetes already at a dilution of 1:6,000,000; in the organism, however, the conditions are different: even with the latter present 500 times more than the concentration just indicated, no therapeutic effect is obtained. In both cases, obviously, O. sharply predominates over parasitotropy. The goal of Ehrlich was to construct preparations which, with maximum parasitotropy, would have minimal O. Atoxil in experiments with the treatment of mice, infected with trypanosomes, with arsenical preparations, proved to be both trypanocidal and toxic; but, by making certain substitutions in its amide group, it was possible to sharply increase the first effect while lowering the second. At the same time, the relationship of the preparations to organs also differed: thus, with one substitution, dancing movements were observed in mice, with another- jaundice, with a third- diarrhea, with a fourth- phenomena from the kidneys. The introduction into the amide group of atoxil of the residue of sulfuric acid led to the annulment of both organotropic and parasitotropic properties. When the chemical structure of the preparation changes, its O. also changes, and both quantitatively and qualitatively: one preparation apparently acted on the cerebellum, another- on the liver, a third- on the intestine, a fourth- on the kidneys. Similarly, with respect to parasites, judging by the effect produced by the preparation, Ehrlich concluded about the existence of either 'arsenoreceptors' (for arsenic), or receptors for substances of the benzidine group, or for triphenylmethane, etc. There are no direct proofs of the existence of chemoreceptors in the protoplasm of cells, since, in contrast to receptors binding toxin or other antigens, they, to use Ehrlich's terminology, do not 'break off' from the cells and do not pass into the blood in the form of antibodies, but Ehrlich draws the corresponding positive conclusion indirectly- from observations on parasitotropy, from the fact, for example, that trypanosomes that have become resistant to any preparation from the arsenic group retain sensitivity to substances from other groups- fuchsin, trypanrot, etc.- When transferring such data, obtained with respect to parasitotropy, to O., one must still note that in multicellular organisms the relationships are more complex: the same Ehrlich, in experiments with vital staining with methylene blue, convinced himself of the importance of the degree of saturation of different parts of the body with oxygen, depending on the peculiarities of blood supply, and in the action of narcotics, according to Meyer and Overton, the so-called coefficient of solubility of the substance in fat and water plays an important role. Adsorption phenomena also play a large role in the distribution of poisons in the organism (see Affinity). Moreover, it is doubtful whether the tetanus toxin is actually fixed in the brain of animals sensitive to it due to the presence of special receptors, or (as others think) here there takes place a process of toxin neutralization by lipoids. However one may relate to Ehrlich's doctrine of receptors in general and chemoreceptors in particular, the problem he raised concerning O. cannot but be recognized as a problem of great importance, both in general biological and in pharmacological-toxicological and chemotherapeutic relations. Before Ehrlich, pharmacology approached the study of medicinal or toxic substances only from the point of view of the connection between composition and action in general; Ehrlich introduced an intermediate link- the question of the distribution of the substance in different parts of the organism. In the field of chemotherapy, it turned out possible to achieve the desired ratio between parasitotropy and O. of a preparation not only by means of such relatively simple substitutions of one grouping by another as in the experiments with atoxil, but also through more complex combinations- the combination of heterogeneous substances, of which one is active, and the other serves as a conductor to certain parts of the organism. Thus, for example, in experiments with chemotherapy of malignant tumors, selenium proved to act destructively on the latter, however only on condition of introduction directly into the tissue of the neoplasm; but when injected into the blood, the selenium preparation does not reach the tumor. When combined with eosin, a substance that easily diffuses throughout the organism, selenium in the form of a complex preparation- selenium eosin- acquired the ability, bypassing other organs and tissues, to be transported to the site of the tumor and thus, under the mentioned conditions, to give the desired effect. Eosin thus, in the mentioned combination, plays the role of a conductor. A similar conductor also turned out to be cantharidin in experiments with chemotherapy of tuberculosis. Cantharidin, when introduced into the animal organism, shows a tendency to accumulate mainly within the limits of inflammatory foci, if such are present, and among other things near tuberculous foci. Hence the idea: to use this peculiarity of cantharidin for the purpose of transporting an active agent to tuberculous foci. As such, some thought to use copper salts (Sakharov), others- gold (Spies), and not without success. The toxicity of cantharidin was reduced by double combination with ethylenediamine, and the new conductor- ethylenediamine cantharidin- with relatively low toxicity retained O. with respect to tuberculous foci (Sakharov). The very fact of O. in this case apparently has to be connected with the increased sensitivity to sharply irritating substances.

In particular, with regard to salvarsan, it should also be borne in mind that the initial opinion about its absolute non-organotropy subsequently proved to be incorrect.