{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T12:48:37Z","timestamp":1762865317565,"version":"3.33.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2007,8,1]],"date-time":"2007-08-01T00:00:00Z","timestamp":1185926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although hypoxia is normal in early pregnancy, low placental oxygen concentrations later in pregnancy are often linked to complications such as pre-eclampsia and intrauterine growth restriction. The effects of low oxygen levels on drug and nutrient uptake via the organic cation transporter OCTN2 has been studied in BeWo cells, an in-vitro model of human trophoblast. BeWo cells were cultured under 20% (control) or 2% O2 (hypoxia) for 48 h before each experiment. In-vitro hypoxia was also simulated by the addition of CoCl2 to the cell culture medium. RT-PCR indicated increased transcription of OCTN2 in BeWo cells cultured under hypoxia, but Western blots did not show a corresponding increase in the amount of OCTN2 protein in the hypoxic cells compared with control. Hypoxia resulted in significant reductions in OCTN2-mediated carnitine uptake. Decreased placental transport of carnitine may lead to symptoms of carnitine deficiency in infants from hypoxic pregnancies, whether caused by high altitude, pre-eclampsia or other factors. The OCTN1 substrate ergothioneine reversed the effects of hypoxia on carnitine transport, but identical concentrations of N-acetylcysteine, another water-soluble intracellular antioxidant, did not have the same effect.<\/jats:p>","DOI":"10.1211\/jpp.59.8.0006","type":"journal-article","created":{"date-parts":[[2007,8,24]],"date-time":"2007-08-24T00:07:47Z","timestamp":1187914067000},"page":"1095-1102","source":"Crossref","is-referenced-by-count":23,"title":["Effects of low oxygen levels on the expression and function of transporter OCTN2 in BeWo cells"],"prefix":"10.1093","volume":"59","author":[{"given":"Erik","family":"Rytting","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth L","family":"Audus","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, The University of Kansas , Lawrence, Kansas 66047,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2007,8,1]]},"reference":[{"key":"2024103109352361100_cit1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0003-9861(91)90158-F","article-title":"The antioxidant action of ergothioneine","volume":"288","author":"Akanmu","year":"1991","journal-title":"Arch. 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Pediatr."},{"key":"2024103109352361100_cit8","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1172\/JCI8316","article-title":"Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3)","volume":"105","author":"Caniggia","year":"2000","journal-title":"J. Clin. Invest"},{"key":"2024103109352361100_cit9","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/S0278-6915(99)00090-3","article-title":"Intracellular antioxidants: from chemical to biochemical mechanisms","volume":"37","author":"Chaudiere","year":"1999","journal-title":"Food Chem. Toxicol."},{"key":"2024103109352361100_cit10","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1210\/me.2004-0162","article-title":"Cobalt chloride-induced estrogen receptor alpha down-regulation involves hypoxia-inducible factor-1alpha in MCF-7 human breast cancer cells","volume":"19","author":"Cho","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"2024103109352361100_cit11","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1079\/BJN20041403","article-title":"Pregnancy increases urinary loss of carnitine and reduces plasma carnitine in Korean women","volume":"93","author":"Cho","year":"2005","journal-title":"Br. J. Nutr."},{"key":"2024103109352361100_cit12","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1183\/09031936.04.00016804","article-title":"Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease","volume":"23","author":"Dekhuijzen","year":"2004","journal-title":"Eur. Respir. J."},{"key":"2024103109352361100_cit13","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/bmb\/ldg005","article-title":"Pre-eclampsia and the hypertensive disorders of pregnancy","volume":"67","author":"Duley","year":"2003","journal-title":"Br. Med. Bull."},{"key":"2024103109352361100_cit14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0143-4004(97)90084-9","article-title":"The effect of hypoxia on human trophoblast in culture: Morphology, glucose transport and metabolism","volume":"18","author":"Esterman","year":"1997","journal-title":"Placenta"},{"key":"2024103109352361100_cit15","doi-asserted-by":"crossref","first-page":"5256","DOI":"10.1073\/pnas.0408624102","article-title":"Discovery of the ergothioneine transporter","volume":"102","author":"Grundemann","year":"2005","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2024103109352361100_cit16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1677\/joe.1.05599","article-title":"Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells","volume":"183","author":"Hayashi","year":"2004","journal-title":"J. Endocrinol."},{"key":"2024103109352361100_cit17","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1210\/en.2005-0416","article-title":"Up-regulation of c-met proto-oncogene product expression through hypoxia-inducible factor-1alpha is involved in trophoblast invasion under low-oxygen tension","volume":"146","author":"Hayashi","year":"2005","journal-title":"Endocrinology"},{"key":"2024103109352361100_cit18","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1079\/PNS2005469","article-title":"Could antioxidant supplementation prevent pre-eclampsia","volume":"64","author":"Holmes","year":"2005","journal-title":"Proc. Nutr. 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Monogr."},{"key":"2024103109352361100_cit29","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1124\/jpet.104.072363","article-title":"Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells","volume":"312","author":"Rytting","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2024103109352361100_cit30","doi-asserted-by":"crossref","first-page":"20378","DOI":"10.1074\/jbc.273.32.20378","article-title":"Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2","volume":"273","author":"Tamai","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2024103109352361100_cit31","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/S0022-3565(24)37280-5","article-title":"Hypoxia inhibits cyclic nucleotide-stimulated epithelial ion transport: Role for nucleotide cyclases as oxygen sensors","volume":"284","author":"Taylor","year":"1998","journal-title":"J. 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