Di-n-butyltin Dichloride Research Articles

Toxicity of organotin compounds: IV. Impairment of energy metabolism of rat thymocytes by various dialkyltin compounds

Isolated thymocytes were incubated with various carbohydrates in the presence of dimethyltindichloride (DMTC), diethyltindichloride (DETC), di- n-butyltindichloride (DBTC), and di- n-octyltindichloride (DOTC) and the substrate conversion, oxygen consumption, and cell viability were measured. All the dialkyltin compounds produced a dose-dependent stimulation of the glucose consumption, but at different concentrations. The most toxic homologs, DBTC and DETC, stimulated the glucose consumption maximally at levels of 5 and 10 μ m, respectively, whereas DMTC and DOTC were less active, inducing a maximum stimulation at 120 μ m. At higher exposure levels a sharp fall in the stimulation of the glucose consumption was noted together with a decrease of the oxygen consumption and viability of the thymocytes. The oxidative metabolism of glucose, lactate, and pyruvate by the TCA cycle was inhibited by dialkyltin compounds in a dose-related fashion. The glycolytic pathway was not affected, since under anaerobic conditions the glucose consumption was similar to that of the controls up to levels inducing a maximum stimulation of the glucose consumption under aerobic conditions. Probably the entrance of the glycolytic end products into the TCA cyle is disturbed by an inhibition of the pyruvate dehydrogenase system. Additional support for an interference with α-keto acid dehydrogenase complexes were obtained from mitochondrial incubations. DBTC inhibited the pyruvate and α-ketoglutarate conversion, oxygen consumption and ATP production of rat liver mitochondria in a dose-related fashion. Although in vitro the dialkyltin homologs display a comparable mode of action on the energy metabolism of rat thymocytes, in vivo especially DBTC and DOTC induce thymus involution whereas DMTC and DETC hardly decrease thymus weight. This discrepancy may be related with a different distribution pattern of the water-soluble lower homologs and the fat-soluble higher homologs. Therefore, we conclude that the inhibition of the energy metabolism of rat thymocytes by dialkyltins is related to their thymolytic effects in vivo.

Lymphocytotoxicity and immunosuppression by organotin compounds. Suppression of graft-versus-host reactivity, blast transformation, and E-rosette formation by Di-n-butyltindichloride and Di-n-Octyltindichloride

Di-n-butyltindichloride (DBTC) and di-n-octyltindichloride (DOTC) represent a new group of organometallic compounds with antilymphocytic properties. In rats they induce lymphocyte depletion in thymus and thymus-dependent areas of spleen and peripheral lymph nodes without signs of myelotoxicity or a generalized toxicity. The number and viability of cells isolated from thymus and peripheral lymphoid organs was severely decreased, whereas the number and viability of bone marrow cells was not reduced. Immunosuppressive properties of DBTC and DOTC are indicated, in this study, by a severe decrease of the graft-versus-host response and the response to the T-cell mitogens phytohemagglutinin and concanavalin A. The T-cell selectivity of these compounds is discussed. In vitro DBTC and DTOC are extremely cytotoxic. Blast transformation of human as well as rat thymocytes was already inhibited at concentrations as low as 0.02 micrograms DBTC (or 0.1 micrograms DOTC) ml medium. Also the E-rosette formation was inhibited at very low drug levels. The similarity of effects upon rat and human lymphocytes suggests that DBTC and DOTC acts in the same manner in rat and man and offers the possibility of a therapeutic use of these compounds.

Immunosuppression induced by certain organotin compounds

Various organotin compounds induce lymphocyte depletion in the lymphoid system especially in the thymus. This report reviews the comparative aspects of the lympholytic activity of various organotins. The immunosuppressive effects of di-n-butyltin-dichloride (DBTC) and di-n-octyltindichloride (DOTC) as well as their in vitro effect upon rat and human lymphocytes are discussed in detail.

Toxicity of organotin compounds. II. Comparative in vivo and in vitro studies with various organotin and organolead compounds in different animal species with special emphasis on lymphocyte cytotoxicity

A series of organotin and organolead compounds were fed to male and female weanling rats for 2 weeks at dietary levels of 0, 50, or 150 ppm, in order to evaluate their toxic effects, with special emphasis on the thymus and peripheral lymphoid organs. A dose-related reduction in the weight of thymus, spleen, and popliteal lymph node, associated with lymphocyte depletion in the cortex of the thymus and the thymus-dependent areas in the peripheral lymphoid organs, was observed in animals fed di-n-octyltin dichloride (DOTC) and di-n-butyltin dichloride (DBTC). As shown previously, these effects were not related to stress. Similar, but less pronounced, lymphoid organ changes occurred in animals fed diets containing diethyltindichloride (DETC) and di-n-propyltindichloride. In contrast, other dialkyltin compounds (dimethyltindichloride; di-n-dodecyltindibromide; and di-n-octadecyltindibromide), as well as mono-n-octyltintrichloride (MOTC), tri-n-octyltinchloride, and tetraoctyltin did not cause atrophy of lymphoid organs. Of the dialkyllead compounds tested, di-n-butylleaddiacetate and di-n-hyxylleaddiacetate, the latter caused distinct lymphoid atrophy, but only when associated with severe growth retardation. A similar structure-activity relationship regarding thymus atrophy by dialkyltin compounds was observed after iv application. DOTC and DBTC were effective at a dose of 1 mg/kg. A dose-related reduction of thymus weight, cell count, and cell viability occurred in rats after a single iv injection of 0, 1, 2, 4, or 8 mg of DOTC/kg. The effect of DOTC was completely reversible. In contrast to rats, lymphoid atrophy did not occur in mice, guinea pigs, or Japanese quail fed DOTC or DBTC. In vitro incubation of thymocytes and bone marrow cells with DBTC and DOTC revealed the same selectivity regarding cell type and species origin of cells as was found in vivo. A dose-related decrease in the survival of rat thymocytes was observed, whereas rat bone marrow cells were not affected by DBTC and DOTC at levels up to 50 μg/ml. In contrast, the number and viability of mouse and guinea pig thymocytes exposed to DBTC were the same as the controls. As the survival of human thymocytes was markedly decreased by DBTC, it possibly acts in the same manner in man and rat. In agreement with in vivo results, the survival of rat thymocytes was not significantly decreased by dimethyltindichloride and diethyltindichloride.