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The ABC transporter Mrp4/Abcc4 is required for Leydig cell protection from chemotherapeutic drugs (844.1)
Author(s) -
Morgan Jessica,
Schuetz John
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.844.1
Subject(s) - pharmacology , programmed cell death , biology , apoptosis , genetics
The thiopurines are widely used to treat a variety of diseases such as pediatric acute lymphoblastic leukemia, adult promyelocytic leukemia, and irritable bowel disease. In both human and rodents, one toxic consequence attributed to 6‐mercaptopurine (6MP) is detrimental reproductive effects related to impaired testosterone (T) production. The ABC transporter Mrp4 plays a protective role against 6MP toxicity as it exports 6MP nucleotide metabolites. As Mrp4 is highly expressed in human and rodent Leydig cells (LCs), we hypothesize it protects LCs against 6MP by extruding nucleotides from cells, promoting LC survival to maintain normal T synthesis. Administration of 6MP to Mrp4+/+ and Mrp4‐/‐ mice produced a strong reduction in LCs, testicular T levels, and increased LC death in Mrp4‐/‐ mice. However, as LCs are post‐mitotic, the mechanism of death is unrelated to 6MP nucleotide incorporation into DNA. We show that cultured Mrp4‐/‐ LCs are highly susceptible to 6MP, exhibiting cytotoxicity at doses 6‐fold lower than Mrp4+/+ LCs. Leydig cell death by 6MP appears to involve a mitochondrial pathway as a pan‐caspase inhibitor blocked 6MP‐mediated death. We will report on the mechanisms of this 6MP‐mediated mitochondrial death. An important implication of our study is humans harboring non‐functional Mrp4 alleles may be at risk for LC toxicity and pathophysiological consequences of reduced T concentrations. Grant Funding Source : This work is supported by grants from the National Institutes of Health (NIH) and ALSAC.