Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier.
Journal
Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
27
10
2021
accepted:
07
03
2022
pubmed:
22
3
2022
medline:
9
6
2022
entrez:
21
3
2022
Statut:
ppublish
Résumé
The blood-testis barrier (BTB) is formed by basal tight junctions between adjacent Sertoli cells (SCs) of the seminiferous tubules and acts as a physical barrier to protect developing germ cells in the adluminal compartment from reproductive toxicants. Xenobiotics, including antivirals, male contraceptives, and cancer chemotherapeutics, are known to cross the BTB, although the mechanisms that permit barrier circumvention are generally unknown. This study used immunohistological staining of human testicular tissue to determine the site of expression for xenobiotic transporters that facilitate transport across the BTB. Organic anion transporter (OAT) 1, OAT2, and organic cation transporter, novel (OCTN) 1 primarily localized to the basal membrane of SCs, whereas OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs) surrounding the seminiferous tubules. Concentrative nucleoside transporter (CNT) 2 localized to Leydig cells (LCs), PMCs, and SC apicolateral membranes. Organic cation transporter (OCT) 1, OCT2, and OCT3 mostly localized to PMCs and LCs, although there was minor staining in developing germ cells for OCT3. Organic anion transporting polypeptide (OATP) 1A2, OATP1B1, OATP1B3, OATP2A1, OATP2B1, and OATP3A1-v2 localized to SC basal membranes with diffuse staining for some transporters. Notably, OATP1C1 and OATP4A1 primarily localized to LCs. Positive staining for multidrug and toxin extrusion protein (MATE) 1 was only observed throughout the adluminal compartment. Definitive staining for CNT1, OAT3, MATE2, and OATP6A1 was not observed. The location of these transporters is consistent with their involvement in the movement of xenobiotics across the BTB. Altogether, the localization of these transporters provides insight into the mechanisms of drug disposition across the BTB and will be useful in developing tools to overcome the pharmacokinetic and pharmacodynamic difficulties presented by the BTB. SIGNIFICANCE STATEMENT: Although the total mRNA and protein expression of drug transporters in the testes has been explored, the localization of many transporters at the blood-testis barrier (BTB) has not been determined. This study applied immunohistological staining in human testicular tissues to identify the cellular localization of drug transporters in the testes. The observations made in this study have implications for the development of drugs that can effectively use transporters expressed at the basal membranes of Sertoli cells to bypass the BTB.
Identifiants
pubmed: 35307651
pii: dmd.121.000748
doi: 10.1124/dmd.121.000748
pmc: PMC9190233
doi:
Substances chimiques
Cations
0
Organic Cation Transporter 1
0
Xenobiotics
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
770-780Subventions
Organisme : NIEHS NIH HHS
ID : P30 ES006694
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM123643
Pays : United States
Organisme : NIEHS NIH HHS
ID : T32 ES007091
Pays : United States
Informations de copyright
Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.
Références
Biopharm Drug Dispos. 2019 Jan;40(1):3-11
pubmed: 30488476
Methods Mol Biol. 2011;763:237-52
pubmed: 21874456
Trends Pharmacol Sci. 2011 Feb;32(2):99-106
pubmed: 21168226
J Pharmacol Exp Ther. 2005 Feb;312(2):601-8
pubmed: 15547112
J Lab Autom. 2015 Apr;20(2):107-26
pubmed: 25586998
Sci Rep. 2019 Dec 24;9(1):19782
pubmed: 31874997
Drug Metab Dispos. 2010 Jan;38(1):168-76
pubmed: 19833843
Xenobiotica. 2006 Oct-Nov;36(10-11):963-88
pubmed: 17118916
Drug Metab Dispos. 2005 Jul;33(7):1062-73
pubmed: 15843488
Endocrinology. 2001 May;142(5):2005-12
pubmed: 11316767
Drug Metab Dispos. 2018 Nov;46(11):1767-1775
pubmed: 30154106
Biol Reprod. 2008 Jun;78(6):1139-52
pubmed: 18218611
Cancer Immun. 2004 Nov 17;4:13
pubmed: 15546177
Gastroenterology. 2001 Feb;120(2):525-33
pubmed: 11159893
Biochem Biophys Res Commun. 2001 Jan 26;280(3):951-9
pubmed: 11162617
Mol Endocrinol. 2002 Oct;16(10):2283-96
pubmed: 12351693
Mol Pharm. 2007 Jul-Aug;4(4):600-7
pubmed: 17616214
J Biochem Mol Toxicol. 2017 Aug;31(8):
pubmed: 28322028
J Exp Clin Cancer Res. 2014 May 11;33:41
pubmed: 24887156
Mol Hum Reprod. 2014 Jun;20(6):476-88
pubmed: 24598113
Cell Transplant. 2011;20(5):619-35
pubmed: 21054948
Reproduction. 2015 Apr;149(4):R169-80
pubmed: 25504871
Biol Reprod. 2002 Dec;67(6):1699-707
pubmed: 12444043
Drug Metab Dispos. 2014 Mar;42(3):469-80
pubmed: 24396146
Prog Histochem Cytochem. 2011 Aug;46(2):49-127
pubmed: 21705043
J Pharmacol Exp Ther. 2000 Jul;294(1):73-9
pubmed: 10871297
Drug Metab Dispos. 2005 Jan;33(1):182-9
pubmed: 15494472
PLoS One. 2016 Mar 03;11(3):e0150143
pubmed: 26938869
Biol Pharm Bull. 2009 Mar;32(3):450-5
pubmed: 19252294
Evid Based Complement Alternat Med. 2015;2015:917670
pubmed: 25788966
J Pharmacol Exp Ther. 2013 Jul;346(1):121-9
pubmed: 23639800
Biochem Pharmacol. 2015 Dec 15;98(4):649-58
pubmed: 26415544
Drug Metab Dispos. 2016 Oct;44(10):1562-8
pubmed: 27504015
Horm Metab Res. 2000 Mar;32(3):87-90
pubmed: 10786925
Biochem Biophys Res Commun. 2021 Jun 18;558:120-125
pubmed: 33910126
J Oral Pathol Med. 2013 Mar;42(3):250-6
pubmed: 22861817
J Pharmacol Exp Ther. 2010 Sep 1;334(3):927-35
pubmed: 20519554
Reproduction. 2005 Jun;129(6):729-36
pubmed: 15923388
Drug Metab Dispos. 2019 Aug;47(8):802-808
pubmed: 31123036
Biochem Biophys Res Commun. 2011 Nov 4;414(4):694-9
pubmed: 21986525
J Histochem Cytochem. 1999 Oct;47(10):1255-64
pubmed: 10490454
Acta Histochem. 2005;107(4):279-89
pubmed: 16139876
Am J Physiol Endocrinol Metab. 2006 May;290(5):E968-75
pubmed: 16368787
Mol Pharmacol. 2021 Feb;99(2):147-162
pubmed: 33262250
J Neurochem. 2019 Feb;148(3):373-385
pubmed: 30295925
Contraception. 2005 Oct;72(4):251-61
pubmed: 16181968
FEBS Lett. 1997 Dec 8;419(1):107-11
pubmed: 9426230
Toxicology. 2013 Aug 9;310:29-38
pubmed: 23707492
Eur J Pharm Sci. 2018 Oct 15;123:277-294
pubmed: 30041030
J Nucl Cardiol. 2021 Oct;28(5):1961-1971
pubmed: 31741324
Int J Biochem Cell Biol. 2009 Dec;41(12):2578-87
pubmed: 19720156
Drug Metab Dispos. 2020 Aug;48(8):622-630
pubmed: 32482756
Endocrinology. 2000 Feb;141(2):710-21
pubmed: 10650953
J Clin Endocrinol Metab. 2002 Apr;87(4):1856-63
pubmed: 11932330
Acta Pharm Sin B. 2019 Sep;9(5):1008-1020
pubmed: 31649850
PLoS One. 2017 Jun 23;12(6):e0180257
pubmed: 28644885
Adv Pharmacol. 2014;71:45-111
pubmed: 25307214
Gastroenterology. 1995 Oct;109(4):1274-82
pubmed: 7557095
Am J Physiol Cell Physiol. 2007 Feb;292(2):C795-806
pubmed: 16971491
Int J Biochem Cell Biol. 2014 Jun;51:111-9
pubmed: 24726739
Biol Reprod. 2011 May;84(5):851-8
pubmed: 21209417
Drug Metab Dispos. 2021 Jul;49(7):479-489
pubmed: 33980604
PLoS Genet. 2015 Nov 05;11(11):e1005581
pubmed: 26539716
Sci Rep. 2018 Feb 8;8(1):2630
pubmed: 29422623
PLoS One. 2013 May 08;8(5):e62638
pubmed: 23667501
Biol Reprod. 2001 May;64(5):1500-8
pubmed: 11319158
Antimicrob Agents Chemother. 2016 Aug 22;60(9):5573-80
pubmed: 27401566
J Endocrinol. 2008 Dec;199(3):351-65
pubmed: 18728126
In Vitro Cell Dev Biol Anim. 1997 Jul-Aug;33(7):516-26
pubmed: 9282312
Mol Cell Endocrinol. 2018 Sep 15;473:217-224
pubmed: 29408603
Exp Eye Res. 2005 Jan;80(1):61-72
pubmed: 15652527
Mol Pharmacol. 2013 Aug;84(2):182-9
pubmed: 23680637
Theranostics. 2020 Feb 18;10(8):3562-3578
pubmed: 32206108
Reproduction. 2005 Jul;130(1):15-28
pubmed: 15985628
Exp Cell Res. 2002 Nov 15;281(1):77-85
pubmed: 12441131
Drug Metab Dispos. 2014 Jan;42(1):89-93
pubmed: 24130369
Biochem J. 1987 Feb 1;241(3):847-55
pubmed: 3109380
Am J Physiol Renal Physiol. 2006 May;290(5):F1118-26
pubmed: 16368738
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2356-60
pubmed: 10051646
Am J Physiol Renal Physiol. 2009 Aug;297(2):F263-71
pubmed: 19515813
Mol Endocrinol. 2003 Jul;17(7):1203-15
pubmed: 12677006
Pharmacol Res Perspect. 2021 Aug;9(4):e00831
pubmed: 34288585
Cell Tissue Res. 2020 Aug;381(2):309-326
pubmed: 32328805
PLoS One. 2016 Feb 09;11(2):e0148739
pubmed: 26859833
FASEB J. 2019 Nov;33(11):12528-12540
pubmed: 31450968
PLoS Pathog. 2020 Jul 2;16(7):e1008601
pubmed: 32614902
J Virol. 2017 Oct 27;91(22):
pubmed: 28878076
Reprod Biomed Online. 2004 Apr;8(4):376-84
pubmed: 15149558
Endocr Rev. 2015 Oct;36(5):564-91
pubmed: 26357922
Drug Metab Dispos. 2020 Jul;48(7):603-612
pubmed: 32393653
PLoS One. 2014 May 19;9(5):e97360
pubmed: 24840500
Pharmaceutics. 2020 Oct 22;12(11):
pubmed: 33105674
Fluids Barriers CNS. 2019 Dec 17;16(1):38
pubmed: 31842924
PLoS One. 2020 Nov 9;15(11):e0241869
pubmed: 33166338
Drug Metab Dispos. 2015 Jun;43(6):829-35
pubmed: 25788542
Eur J Cancer. 2004 Sep;40(14):2064-70
pubmed: 15341980
Pflugers Arch. 2004 Feb;447(5):728-34
pubmed: 12856181
Drug Metab Dispos. 2011 Dec;39(12):2395-402
pubmed: 21878559
J Invest Dermatol. 2017 Mar;137(3):595-602
pubmed: 27826008
Biol Reprod. 2008 Jun;78(6):1127-38
pubmed: 18218612
Am J Physiol Renal Physiol. 2016 Jan 1;310(1):F57-67
pubmed: 26538438
PLoS One. 2011;6(9):e24738
pubmed: 21935449
Dev Biol. 2005 Nov 1;287(1):111-24
pubmed: 16185683
Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5256-61
pubmed: 15795384