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Hematoxylin and eosin–stained paraffin sections of testis and epididymis from ETOPOPHOS-treated wild-type and mrp1-deficient mice.  Wild-type (A and C) and mrp1-deficient (B and D) mice 7 d after ETOPOPHOS administration. (A and B) Sections of the testis showing vacuoles and  disrupted spermatogenesis (B). (C and D) Sections of the epididymis showing reduced numbers of intact spermatids in the lumen (D). Bar, 100 μm.
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Figure 2: Hematoxylin and eosin–stained paraffin sections of testis and epididymis from ETOPOPHOS-treated wild-type and mrp1-deficient mice. Wild-type (A and C) and mrp1-deficient (B and D) mice 7 d after ETOPOPHOS administration. (A and B) Sections of the testis showing vacuoles and disrupted spermatogenesis (B). (C and D) Sections of the epididymis showing reduced numbers of intact spermatids in the lumen (D). Bar, 100 μm.

Mentions: Spermatogenesis is a tightly organized differentiation process in the seminiferous tubules that occurs according to a cycle of subsequent stages, with specific cell associations at different cross sections of the testicular tubules (the spermatogenic cycle). Histological sections stained with hematoxylin and eosin indicated that the testis of drug-treated mutant mice showed largely distorted spermatogenesis with no signs of meiotic divisions (Fig. 2, A and B), and an increased number of prematurely released round germ cells, including many spermatids, with very few spermatozoa in the epididymis (Fig. 2, C and D). The testis of drug-treated wild-type mice showed a partially distorted spermatogenesis, but meiotic divisions still occurred and the epididymis contained many spermatozoa and several prematurely released round germ cells. These findings indicate that mrp1 could play a direct protective role in the blood–testis barrier.

Multidrug Resistance Protein 1 Protects the Oropharyngeal Mucosal Layer and the Testicular Tubules against Drug-induced Damage

Wijnholds J, Scheffer GL, van der Valk M, van der Valk P, Beijnen JH, Scheper RJ, Borst P - J. Exp. Med. (1998)

Bottom Line: Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR).We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis.Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.

Affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam.

ABSTRACT
The multidrug resistance protein 1 (MRP1) gene encodes a transporter protein that helps to protect cells against xenobiotics. Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the toxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1(-/-) mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the basal layers of the oropharyngeal mucosa and in the basal membrane of the Sertoli cells in the testis apparently protect wild-type mice against this tissue damage. We also find drug-induced polyuria in mrp1(-/-) mice, which correlates with the presence of mrp1 protein in the urinary collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.

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