Histological and toxicological evaluation, in rat, of a P-glycoprotein inducer and activator: 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5)

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Carolina Rocha-Pereira
Vera Silva
Vera Marisa Costa
Renata Silva
Juliana Garcia
Salomé Gonçalves-Monteiro
Margarida Duarte-Araújo
Alice Santos-Silva
Susana Coimbra
Ricardo Jorge Dinis-Oliveira
Catarina Lopes
Paula Silva
Solida Long
Emília Sousa
Maria de Lourdes Bastos
Fernando Remião


P-glycoprotein (P-gp) is an ATP-binding cassette transporter involved in the efflux of numerous compounds that influences the pharmacokinetics of xenobiotics. It reduces intestinal absorption and exposure of target cells to toxicity. Thioxanthones are compounds able to induce and/or activate P-gp in vitro. Particularly, 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5) behaves as a P-gp inducer and activator in vitro. The aims of this study were: i) to perform a histological characterization, by testing a single high dose of TX5 [30 mg/kg, body weight (b.w.), gavage], administered to Wistar Han rats, 24 hours after administration; and ii) to perform both a complete histological characterization and a preliminary safety evaluation, in distinct target organs, 24 hours after administration of a single lower dose of TX5 (10 mg/kg, b.w., gavage) to Wistar Han rats. The results showed a relevant histological toxicity for the higher dose of TX5 administered (30 mg/kg, b.w.), manifested by extensive hepatic necrosis and splenic toxicity (parenchyma with hyperemia, increased volume of both white and red pulp, increased follicles marginal zone). Moreover, in the kidneys, a slight hyperemia and tubular edema were observed in TX5-treated animals, as well as an inflammation of the small intestine. On the contrary, for the lower tested dose (10 mg/kg, b.w.), we did not observe any relevant histological toxicity in the evaluated organs. Additionally, no significant differences were found in the ATP levels between TX5-exposed and control animals in any of the evaluated organs, with the exception of the intestine, where ATP levels were significantly higher in TX5-treated rats. Similarly, TX5 caused a significant increase in the ratio GSH/GSSG only in the lungs. TX5 (10 mg/kg, b.w.) did not induce any change in any of the hematological and biochemical circulating evaluated parameters. However, TX5 was able to significantly reduce the activated partial thromboplastin time, without affecting the prothrombin time. The urine biochemical analysis revealed a TX5-mediated increase in both creatinine and sodium. Taken together, our results show that TX5, at a dose of 10 mg/kg, does not induce considerable toxicity in the biological matrices studied. Given this adequate safety profile, TX5 becomes a particularly interesting compound for ex vivo and in vivo studies, regarding the potential for induction and activation of P-gp at the intestinal barrier.

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Rocha-Pereira, C., Silva, V., Costa, V., Silva, R., Garcia, J., Gonçalves-Monteiro, S., Duarte-Araújo, M., Santos-Silva, A., Coimbra, S., Dinis-Oliveira, R., Lopes, C., Silva, P., Long, S., Sousa, E., de Lourdes Bastos, M., & Remião, F. (2019). Histological and toxicological evaluation, in rat, of a P-glycoprotein inducer and activator: 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5). EXCLI Journal, 18, 697-722. https://doi.org/10.17179/excli2019-1675
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