Characterization of human liver thermostable phenol sulfotransferase (SULT1A1) allozymes with 3,3',5-triiodothyronine as the substrate

Li, X.; Clemens, Dahn L.; Cole, Jim

doi:10.1677/joe.0.1710525

Cited by 33 publications

(14 citation statements)

References 38 publications

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“…In previous studies, hSULT1A1, -1A2, -1A3, -1B1, -1C1, and -1E1 have been identified as important enzymes for iodothyronine sulfation in humans (1,13,23,28,29,47). rSULT1A1, -1B1, -1C1, and -1E1 show 79, 74, 63, and 70% amino acid sequence identity, respectively, with their human homologs, and ϳ50% identity among themselves.…”

Section: Discussionmentioning

confidence: 97%

Characterization of rat iodothyronine sulfotransferases

Kester¹,

Kaptein²,

Roest³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Sulfation appears to be an important pathway for the reversible inactivation of thyroid hormone during fetal development. The rat is an often used animal model to study the regulation of fetal thyroid hormone status. The present study was done to determine which sulfotransferases (SULTs) are important for iodothyronine sulfation in the rat, using radioactive T 4, T3, rT3, and 3,3Ј-T2 as substrates, 3Ј-phosphoadenosine-5Ј-phosphosulfate (PAPS) as cofactor, and rat liver, kidney and brain cytosol, and recombinant rat SULT1A1, -1B1, -1C1, -1E1, -2A1, -2A2, and -2A3 as enzymes. Recombinant rat SULT1A1, -1E1, -2A1, -2A2, and -2A3 failed to catalyze iodothyronine sulfation. For all tissue SULTs and for rSULT1B1 and rSULT1C1, 3,3Ј-T 2 was by far the preferred substrate. Apparent K m values for 3,3Ј-T2 amounted to 1.9 M in male liver, 4.4 M in female liver, 0.76 M in male kidney, 0.23 M in male brain, 7.7 M for SULT1B1, and 0.62 M for SULT1C1, whereas apparent K m values for PAPS showed less variation (2.0-6.9 M). Sulfation of 3,3Ј-T 2 was inhibited dose dependently by other iodothyronines, with similar structure-activity relationships for most enzymes except for the SULT activity in rat brain. The apparent K m values of 3,3Ј-T2 in liver cytosol were between those determined for SULT1B1 and -1C1, supporting the importance of these enzymes for the sulfation of iodothyronines in rat liver, with a greater contribution of SULT1C1 in male than in female rat liver. The results further suggest that rSULT1C1 also contributes to iodothyronine sulfation in rat kidney, whereas other, yet-unidentified forms appear more important for the sulfation of thyroid hormone in rat brain. thyroid hormone; sulfation; rat sulfotransferase 1B1; rat sulfotransferase 1C1 SULFATION IS A METABOLIC REACTION that facilitates the excretion of endogenous and exogenous hydrophobic compounds in bile and urine by increasing their water solubility (5,9,16,35). Biliary excretion of iodothyronines is also increased by sulfation. More importantly, however, sulfation appears to be a key step in the inactivation of thyroid hormone. The prohormone thyroxine (T 4 ) is converted by outer-ring deiodination (ORD) to the biologically active 3,3Ј,5-triiodothyronine (T 3 ) or by inner-ring deiodination (IRD) to the inactive 3,3Ј,5Ј-triiodothyronine (rT 3 ) (42). By sulfation, T 3 loses its affinity for the thyroid hormone receptors (41). Additionally, T 3 sulfate (T 3 S) is subject to accelerated degradation, as sulfation facilitates the IRD of T 3 by the type I deiodinase (D1) (42). Sulfation also facilitates the inactivating IRD of T 4 by D1, whereas the activating ORD of T 4 by D1 is completely blocked by sulfation (42). Therefore, an important function of sulfation is to facilitate the irreversible degradation of thyroid hormone. Furthermore, under conditions in which the deiodinative clearance of sulfates is impaired, sulfation may be reversed by sulfatases. Because T 3 S and T 4 S levels in the human fetal circulation are high (4, 38, 40), it has been speculated ...

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Section: Discussionmentioning

confidence: 97%

Characterization of rat iodothyronine sulfotransferases

Kester¹,

Kaptein²,

Roest³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…Experiments with the recombinant proteins have, in the main, failed to show significant differences in kinetic properties between SULTs 1A1 * 1 and 1A1 * 2, although the thermal stability of the SULT1A1 * 2 allozyme appears considerably reduced compared to the wild-type enzyme. 53,55,56 Recent work from this laboratory using recombinant enzymes expressed and purified from E. coli suggests that the 1A1 * 2 allozyme may be a more catalytically efficient enzyme, and it is certainly considerably less susceptible to the partial substrate inhibition phenomenon displayed by SULT1A1 * 1 (Tabrett CA and Coughtrie MWH, unpublished work). However, the 1A1 * 2 allozyme protein appears to have a shorter biological halflife than the wild-type, and preliminary data suggest that it is more readily degraded via the proteasome pathway.…”

Section: Sult1a1 Pharmacogeneticsmentioning

confidence: 99%

Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

2002

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Members of the cytosolic sulfotransferase (SULT) superfamily catalyse the sulfation of a multitude of xenobiotics, hormones and neurotransmitters. Humans have at least 10 functional SULT genes, and a number of recent advances reviewed here have furthered our understanding of SULT function. Analysis of expression patterns has shown that sulfotransferases are highly expressed in the fetus, and SULTs may in fact be a major detoxification enzyme system in the developing human. The X-ray crystal structures of three SULTs have been solved and combined with mutagenesis experiments and molecular modelling, they have provided the first clues as to the factors that govern the unique substrate specificities of some of these enzymes. In the future these and other studies will facilitate prediction of the fate of chemicals metabolised by sulfation. Variation in sulfation capacity may be important in determining an individual's response to xenobiotics, and there has been an explosion in information on sulfotransferase polymorphisms and their functional consequences, including the influence of SULT1A1 genotype on susceptibility to colorectal and breast cancer. Finally, the first gene knockout experiments with SULTs have recently been described, with the generation of estrogen sulfotransferase deficient mice in which reproductive capacity is compromised. Our improved understanding of these enzymes will have significant benefits in such diverse areas as drug design and development, cancer susceptibility, reproduction and development.

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“…This may reflect the differential nature of the substrate binding pocket of these isoforms (Gamage et al, 2003). The SULT1A1 binding pocket accepts a wide range of molecules, such as simple planar-substituted phenols (Brix et al, 1999), as well as very large lipophilic substrates (Harris et al, 2000;Li et al, 2001) and polycyclic aromatic compounds (Grimm et al, 2013). Lorcaserin is a secondary amine-containing benzazepine that is more lipophilic due to the aryl chloride portion of the molecule and thereby may be well suited for binding to the hydrophobic pocket of SULT1A1.…”

Section: Discussionmentioning

confidence: 99%

Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation

Sadeque

Palamar

Usmani

et al. 2016

Drug Metabolism and Disposition

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Lorcaserin [(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine] hydrochloride hemihydrate, a selective serotonin 5-hydroxytryptamine (5-HT) 5-HT 2C receptor agonist, is approved by the U.S. Food and Drug Administration for chronic weight management. Lorcaserin is primarily cleared by metabolism, which involves multiple enzyme systems with various metabolic pathways in humans. The major circulating metabolite is lorcaserin N-sulfamate. Both human liver and renal cytosols catalyze the formation of lorcaserin N-sulfamate, where the liver cytosol showed a higher catalytic efficiency than renal cytosol. Human sulfotransferases (SULTs) SULT1A1, SULT1A2, SULT1E1, and SULT2A1 are involved in the formation of lorcaserin N-sulfamate. The catalytic efficiency of these SULTs for lorcaserin N-sulfamate formation is widely variable, and among the SULT isoforms SULT1A1 was the most efficient. The order of intrinsic clearance for lorcaserin N-sulfamate is SULT1A1 > SULT2A1 > SULT1A2 > SULT1E1. Inhibitory effects of lorcaserin N-sulfamate on major human cytochrome P450 (P450) enzymes were not observed or minimal. Lorcaserin N-sulfamate binds to human plasma protein with high affinity (i.e., >99%). Thus, despite being the major circulating metabolite, the level of free lorcaserin N-sulfamate would be minimal at a lorcaserin therapeutic dose and unlikely be sufficient to cause drug-drug interactions. Considering its formation kinetic parameters, high plasma protein binding affinity, minimal P450 inhibition or induction potential, and stability, the potential for metabolic drug-drug interaction or toxicological effects of lorcaserin N-sulfamate is remote in a normal patient population.

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Characterization of human liver thermostable phenol sulfotransferase (SULT1A1) allozymes with 3,3',5-triiodothyronine as the substrate

Cited by 33 publications

References 38 publications

Characterization of rat iodothyronine sulfotransferases

Characterization of rat iodothyronine sulfotransferases

Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation

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