Revision of the affinity constant for perchlorate binding to the sodium‐iodide symporter based on in vitro and human in vivo data

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, K . 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. K 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 K , 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 day . Thus, this lower K value both fits the in vitro NIS kinetics and provides better predictions of human in vivo RAIU data. This change in K 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.

Adverse Outcome Pathway on inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment

“…Recent revision of the affinity constant for perchlorate binding to the NIS symporter based on in vitro and human in vivo data, performed by refitting published in vitro data, in which perchlorate-induced inhibition of iodide uptake via the NIS was measured, yielding a Michaelis-Menten kinetic constant (Km) of 1.5 μm, showed that a 60% lower value for the Km, equal to 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 (Schlosser PM, 2016).…”

A comparison of thyroidal protection by stable iodine or perchlorate in the case of acute or prolonged radioiodine exposure

“…In the case of iodine blockade, the two competing entities are chemically identical (radioiodine and stable iodine) and share the same Michaelis–Menten constant ( K m = 9 µmol l −1 ). For perchlorate, the Michaelis–Menten constant has been given with 1.5 µmol l −1 (Kosugi et al 1996 ), but a revised lower value of 0.59 µmol l −1 was reported recently with the indication that the latter was better suited to describe the kinetics of lower dose levels below 100 µg kg −1 day −1 (Schlosser 2016 ). When validating our model using empirical data, we used both constants to identify the value actually better suited to study protective effects against radioiodine exposure.…”

“…In addition, we used the complete combined perchlorate-radioiodine model with competition at the carrier site to compute the protective efficacy after the experimental administration of radioiodine (iodine-123) to volunteers as described in several studies (Lawrence et al 2000 ; Greer et al 2002 ; Bravermann et al 2005 ; Hänscheid et al 2011 ) and compared our results with the measured values reported. Computations were performed for Michaelis–Menten constants for perchlorate described in the literature: 1.5 µmol l −1 (Kosugi et al 1996 ) or 0.59 µmol l −1 , as recently reported for lower dosages up to 100 µg kg −1 day −1 (Schlosser 2016 ).…”

Inter-species variation in monovalent anion substrate selectivity and inhibitor sensitivity in the sodium iodide symporter (NIS)

“…NIS exclusively transports monovalent anions, encompassing a wide range of substrates including BF 4 -, TcO 4 -, and SCN - (Table 1. References reporting uptake, inhibition, stoichiometry and K m : [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. References reporting fresh and seawater anion concentrations: .)…”

“…In rat NIS, iodide is transported with a K m value of 9.7-33 μM [13,16,17]. [13,16,18]. No mechanism has been identified to explain the different affinities for these chemically similar anions.…”