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Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road
Accepted Manuscript Title: Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road Author: Amr Ahmed EL-Arabey PII: DOI: Reference:
S0300-483X(17)30167-1 http://dx.doi.org/doi:10.1016/j.tox.2017.05.020 TOX 51893
To appear in:
Toxicology
Received date:
23-5-2017
Please cite this article as: EL-Arabey, Amr Ahmed, Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road.Toxicology http://dx.doi.org/10.1016/j.tox.2017.05.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road Amr Ahmed EL-Arabey1,2,* 1
Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University,
Egypt; 2CAS-TWAS Fellowship at University of Science and Technology of China, China *
[email protected];
Email:
[email protected]
To the Editor: Cisplatin (CP) is an inorganic platinum chemotherapeutic agent that is widely used in the treatment of a variety of solid malignant tumors such as head and neck, lung, ovarian, testis and bladder cancers. Practically, Nephrotoxicity is the main dose limiting side effect of CP [1]. Yet, in spite of intense efforts over the ensuing decades to find less toxic but equally effective alternatives, CP continues to be widely prescribed. CP is sex related; greater intensity of damage in male than female and these differences may be related to CP uptake by Organic cation transporter 2 (OCT2) due to the markedly higher OCT2 renal expression in male than female rats [2]. Recently, I suggested that the main determinant for sex differences in OCT2 gene expression is related to testosterone [3]. Moreover, study demonstrated that OCT2 level was significantly reduced in mice after castration [4]. Furthermore, CP therapy should be avoided when serum testosterone level is high because the
high
concentrations
of
testosterone
promote
CP-induced
nephrotoxicity [5]. Hence, the regulation of OCT2 expression represents as an ideal target to mediate CP induced nephrotoxicity. Recently, study deduced that formononetin reduced the nephrotoxicity by decreasing the accumulation of CP in renal tubular cells through decrease expression of OCT2 and increasing multidrug resistance-associated proteins (Mrp2 and Mrp4) expressions [6]. Several studies demonstrated that formononetin is testosterone 5 alpha -reductase inhibitor [7]. Testosterone has been shown to implicate up regulation of thromboxane A2 (TXA2) receptor density in several cell types via dihydrotestosterone (DHT). In addition, testosterone is reduced at the 5 alpha position to its active metabolite, DHT, by 5 alpha-reductase. Furthermore, study deduced that epristeride, a 5 alphareductase inhibitor decreased TXA2 receptor density in aortic membranes [8]. Hence, I suggest that formononetin reduced expression of OCT2 through DHT pathway. In addition, I would like to shed light on one more substantial future work direction to overcome the main dosing limiting nephrotoxic effect of CP through further works on the gender regulation of OCT2 expression to reveal additional inhibitors of OCT2 and to improve the current situation of CP nephrotoxic effect.
Reference List 1 Sastry J, Kellie SJ: Severe neurotoxicity, ototoxicity and nephrotoxicity following highdose cisplatin and amifostine. Pediatr Hematol Oncol 2005;22:441-445. 2 El-Arabey AA: Gender difference in Cisplatin-induced nephrotoxicity in a rat model. Nephrourol Mon 2015;7:e23595.
3 El-Arabey AA: Sex and age differences related to renal OCT2 gene expression in cisplatin-induced nephrotoxicity. Iran J Kidney Dis 2015;9:335-336. 4
Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V: Regulatory role of testosterone in organic cation transport: in vivo and in vitro studies. Biol Pharm Bull 2009;32:982-987.
5
Rostami B, Nematbakhsh M, Pezeshki Z, Talebi A, Sharifi MR, Moslemi F, EshraghiJazi F, Ashrafi F: Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats. Nephrourol Mon 2014;6:e21546.
6
Huang D, Wang C, Duan Y, Meng Q, Liu Z, Huo X, Sun H, Ma X, Liu K: Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol Appl Pharmacol 2017;326:15-24.
7 Bae M, Woo M, Kusuma IW, Arung ET, Yang CH, Kim YU: Inhibitory effects of isoflavonoids on rat prostate testosterone 5alpha-reductase. J Acupunct Meridian Stud 2012;5:319-322. 8 Higashiura K, Blaney B, Morgan E, Mathur RS, Halushka PV: Inhibition of testosterone 5 alpha-reductase: evidence for tissue-specific regulation of thromboxane A2 receptors. J Pharmacol Exp Ther 1996;279:1386-1391.
S0300-483X(17)30167-1 http://dx.doi.org/doi:10.1016/j.tox.2017.05.020 TOX 51893
To appear in:
Toxicology
Received date:
23-5-2017
Please cite this article as: EL-Arabey, Amr Ahmed, Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road.Toxicology http://dx.doi.org/10.1016/j.tox.2017.05.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road Amr Ahmed EL-Arabey1,2,* 1
Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University,
Egypt; 2CAS-TWAS Fellowship at University of Science and Technology of China, China *
[email protected];
Email:
[email protected]
To the Editor: Cisplatin (CP) is an inorganic platinum chemotherapeutic agent that is widely used in the treatment of a variety of solid malignant tumors such as head and neck, lung, ovarian, testis and bladder cancers. Practically, Nephrotoxicity is the main dose limiting side effect of CP [1]. Yet, in spite of intense efforts over the ensuing decades to find less toxic but equally effective alternatives, CP continues to be widely prescribed. CP is sex related; greater intensity of damage in male than female and these differences may be related to CP uptake by Organic cation transporter 2 (OCT2) due to the markedly higher OCT2 renal expression in male than female rats [2]. Recently, I suggested that the main determinant for sex differences in OCT2 gene expression is related to testosterone [3]. Moreover, study demonstrated that OCT2 level was significantly reduced in mice after castration [4]. Furthermore, CP therapy should be avoided when serum testosterone level is high because the
high
concentrations
of
testosterone
promote
CP-induced
nephrotoxicity [5]. Hence, the regulation of OCT2 expression represents as an ideal target to mediate CP induced nephrotoxicity. Recently, study deduced that formononetin reduced the nephrotoxicity by decreasing the accumulation of CP in renal tubular cells through decrease expression of OCT2 and increasing multidrug resistance-associated proteins (Mrp2 and Mrp4) expressions [6]. Several studies demonstrated that formononetin is testosterone 5 alpha -reductase inhibitor [7]. Testosterone has been shown to implicate up regulation of thromboxane A2 (TXA2) receptor density in several cell types via dihydrotestosterone (DHT). In addition, testosterone is reduced at the 5 alpha position to its active metabolite, DHT, by 5 alpha-reductase. Furthermore, study deduced that epristeride, a 5 alphareductase inhibitor decreased TXA2 receptor density in aortic membranes [8]. Hence, I suggest that formononetin reduced expression of OCT2 through DHT pathway. In addition, I would like to shed light on one more substantial future work direction to overcome the main dosing limiting nephrotoxic effect of CP through further works on the gender regulation of OCT2 expression to reveal additional inhibitors of OCT2 and to improve the current situation of CP nephrotoxic effect.
Reference List 1 Sastry J, Kellie SJ: Severe neurotoxicity, ototoxicity and nephrotoxicity following highdose cisplatin and amifostine. Pediatr Hematol Oncol 2005;22:441-445. 2 El-Arabey AA: Gender difference in Cisplatin-induced nephrotoxicity in a rat model. Nephrourol Mon 2015;7:e23595.
3 El-Arabey AA: Sex and age differences related to renal OCT2 gene expression in cisplatin-induced nephrotoxicity. Iran J Kidney Dis 2015;9:335-336. 4
Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V: Regulatory role of testosterone in organic cation transport: in vivo and in vitro studies. Biol Pharm Bull 2009;32:982-987.
5
Rostami B, Nematbakhsh M, Pezeshki Z, Talebi A, Sharifi MR, Moslemi F, EshraghiJazi F, Ashrafi F: Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats. Nephrourol Mon 2014;6:e21546.
6
Huang D, Wang C, Duan Y, Meng Q, Liu Z, Huo X, Sun H, Ma X, Liu K: Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol Appl Pharmacol 2017;326:15-24.
7 Bae M, Woo M, Kusuma IW, Arung ET, Yang CH, Kim YU: Inhibitory effects of isoflavonoids on rat prostate testosterone 5alpha-reductase. J Acupunct Meridian Stud 2012;5:319-322. 8 Higashiura K, Blaney B, Morgan E, Mathur RS, Halushka PV: Inhibition of testosterone 5 alpha-reductase: evidence for tissue-specific regulation of thromboxane A2 receptors. J Pharmacol Exp Ther 1996;279:1386-1391.