Revision of the affinity constant for perchlorate binding to the sodium-iodide symporter based on in vitro and human in vivo data.
J Appl Toxicol
; 36(12): 1531-1535, 2016 12.
Article
em En
| MEDLINE
| ID: mdl-27177048
ABSTRACT
A series of previously published physiologically based pharmacokinetic (PBPK) models describe the effect of perchlorate on iodide uptake by the thyroid, with the mechanism being competitive inhibition of iodide transport by the sodium-iodide symporter (NIS). Hence a key parameter of these models is the affinity of perchlorate for the NIS, characterized as the Michaelis-Menten kinetic constant, Km . However, when model predictions were compared to published results of a human study measuring radio-iodide uptake (RAIU) inhibition after controlled perchlorate exposures, it was found to only fit the lowest exposure level and underpredicted RAIU inhibition at higher levels. Published in vitro data, in which perchlorate-induced inhibition of iodide uptake via the NIS was measured, were re-analyzed. Km for binding of perchlorate to the NIS originally derived from these data, 1.5 µm, had been obtained using Lineweaver-Burk plots, which allow for linear regression but invert the signal-noise of the data. Re-fitting these data by non-linear regression of the non-inverted data yielded a 60% lower value for the Km , 0.59 µm. Substituting this value into the PBPK model for an average adult human significantly improved model agreement with the human RAIU data for exposures <100 µg kg-1 day-1 . Thus, this lower Km value both fits the in vitro NIS kinetics and provides better predictions of human in vivo RAIU data. This change in Km increases the predicted sensitivity of humans to perchlorate over twofold for low-level exposures. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glândula Tireoide
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Percloratos
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Simportadores
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Iodetos
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Modelos Biológicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article