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Thyronamines Are Substrates for Human Liver Sulfotransferases

Veterans Affairs Medical Center (C.A.P., R.J.A.), Omaha, Nebraska 68105; University of California, San Francisco (T.S.S.), San Francisco, California 94143; and Creighton University Medical Center (R.J.A.), Omaha, Nebraska 68131

Address all correspondence and requests for reprints to: Robert J. Anderson, M.D., Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska 68105. E-mail: Robert.Anderson4{at}va.gov.

Sulfotransferases (SULTs) catalyze the sulfation of many endogenous compounds that include monoamine neurotransmitters, such as dopamine (DA), and thyroid hormones (iodothyronines). Decarboxylation of iodothyronines results in formation of thyronamines. In the mouse, thyronamines act rapidly in a nongenomic fashion to initiate hypothermia and decrease cardiac output and heart rate. These effects are attenuated after 1–4 h, and metabolism of thyronamines via sulfation may be a mechanism for termination of thyronamine action. We carried out this study to test thyronamine (T₀AM), 3-iodothyronamine (T₁AM), 3,5-diiodothyronamine (T₂AM), and 3,5,3'-triiodothyronamine (T₃AM) as substrates for human liver and cDNA-expressed SULT activities. We characterized several biochemical properties of SULTs using the thyronamines that acted as substrates for SULT activities in a human liver high-speed supernatant pool (n = 3). T₁AM led to the highest SULT activity. Activities with T₀AM and T₃AM were 10-fold lower, and there was no detectable activity with T₂AM. Thyronamines were then tested as substrates with eight cDNA-expressed SULTs (1A1, 1A2, 1A3, 1C2, 1E1, 2A1, 2B1a, and 2B1b). Expressed SULT1A3 had the greatest activity with T₀AM, T₁AM, and T₃AM, whereas SULT1A1 showed similar activity only with T₃AM. Expressed SULT1E1 had low activity with each substrate. T₁AM, the most active thyronamine pharmacologically, was associated with the greatest SULT activity of the thyronamines tested in the liver pool and in both the expressed SULT1A3 and SULT1E1 preparations. Our results support the conclusion that sulfation contributes to the metabolism of thyronamines in human liver and that SULT activities may regulate the physiological effects of endogenous thyronamines.

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