Sulfation of ractopamine and salbutamol by the human cytosolic sulfotransferases

Abstract

-Cheh Liu *These two authors contributed equally to this study.Feed additives such as ractopamine and salbutamol are pharmacologically active compounds, acting primarily as b-adrenergic agonists. This study was designed to investigate whether the sulfation of ractopamine and salbutamol may occur under the metabolic conditions and to identify the human cytosolic sulfotransferases (SULTs) that are capable of sulfating two major feed additive compounds, ractopamine and salbutamol. A metabolic labelling study showed the generation and release of [ 35 S]sulfated ractopamine and salbutamol by HepG2 human hepatoma cells labelled with [ 35 S]sulfate in the presence of these two compounds. A systematic analysis using 11 purified human SULTs revealed SULT1A3 as the major SULT responsible for the sulfation of ractopamine and salbutamol. The pH dependence and kinetic parameters were analyzed. Moreover, the inhibitory effects of ractopamine and salbutamol on SULT1A3-mediated dopamine sulfation were investigated. Cytosol or S9 fractions of human lung, liver, kidney and small intestine were examined to verify the presence of ractopamine-/ salbutamol-sulfating activity in vivo. Of the four human organs, the small intestine displayed the highest activity towards both compounds. Collectively, these results imply that the sulfation mediated by SULT1A3 may play an important role in the metabolism and detoxification of ractopamine and salbutamol.

Impact of SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of phenylephrine and salbutamol by human SULT1A3 allozymes

“…Specific activities of wild-type and SULT1A3 allozymes were determined using two different substrate concentrations, one approximately ten times lower than the reported K m and the other close to the reported K m of the wild-type SULT1A3 with phenylephrine or salbutamol as substrate [8,9]. Results obtained are shown in Figures 1 and 2.…”

“…Phenylephrine and salbutamol are drugs that are prescribed for treating patients suffering from a number of diseases/disorders, including nasal and sinus congestion, hypotension, asthma and COPD [1][2][3]5]. Pharmacokinetic studies have demonstrated that both these two drugs are metabolized through sulfation in human body under the action of SULTs, particularly SULT1A3 [4,[7][8][9]. Considering the critical role SULT1A3 in their metabolism, we were interested in examining the effects of genetic polymorphism on the sulfating activity of SULT1A3 allozymes toward phenylephrine and salbutamol.…”

“…Approximately 47% of phenylephrine and 20-60% of salbutamol administered orally have been shown to be subjected to sulfation [4,7]. Studies have revealed that of the thirteen human cytosolic sulfotransferases (SULTs), SULT1A3 was the major SULT responsible for the sulfation of both these two drugs [8,9]. It has been reported that orally administered salbutamol and other β2 agonists, although well absorbed from the gastrointestinal tract, may undergo extensive presystemic sulfation in the liver and intestine, leading to their inactivation and low systemic bioavailability [6,[10][11][12].…”

“…The SULT enzymes catalyze the transfer of a sulfonate group from the 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyl or amino group of an acceptor substrate compound [16]. As noted above, SULT1A3 has been shown to be responsible for the sulfation of phenylephrine and salbutamol [8,9]. Previous genomic studies have demonstrated the duplication of the gene encoding SULT1A3 during evolution process [17,18].…”

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

“…Красноречивым примером хиральной инверсии и ее потенциально неблагоприятного клинического значения у человека является талидомид, энантиомеры которого быстро подвергаются рацемизации in vivo и ассоциируются с хорошо известными тератогенными эффектами талидомида (Zhou et al, 2015). Ko et al (2012) в эксперименте in vitro с применением культуры клеток гепатомы человека HepG2 подтвердили роль сульфатирования в печени как основного механизма биотрансформации сальбутамола у человека, оценивавшегося по интенсивности генерации 35 S-меченого сульфата. В ходе тестирования специфической активности 11 рекомбинантных изоформ SULT человека установлено, что SULT1A3 играет преференциальную роль в метаболизме и детоксикации сальбутамола.…”