Triclosan as a substrate and inhibitor of 3′-phosphoadenosine-5′-phosphosulfate-sulfotransferase and UDP-glucuronosyl transferase in human liver fractions

Triclosan is a broad spectrum antibacterial agent used in many household products. Due to its structural similarity to polychlorobiphenylols, which are potent inhibitors of the sulfonation and glucuronidation of 3-hydroxy-benzo[a] pyrene, it was hypothesized that triclosan would inhibit these phase II enzymes. This study was designed to assess the interactions of triclosan as a substrate and inhibitor of 3'-phosphoadenosine 5'-phosphosulfate-sulfotransferases and UDP-glucuronosyltransferases in human liver cytosol and microsomes. Triclosan was sulfonated and glucuronidated in human liver. The apparent K-m and V-max values for triclosan sulfonation were 8.5 muM and 0.096 nmol/min/mg protein, whereas K-m and V-max values for glucuronidation were 107 muM and 0.739 nmol/min/mg protein. Triclosan inhibited the hepatic cytosolic sulfonation of 3-hydroxybenzo(a) pyrene (3-OH-BaP), bisphenol A, p-nitrophenol, and acetaminophen with IC50 concentrations of 2.87, 2.96, 6.45, and 17.8 muM, respectively. Studies of 3-OH-BaP sulfonation by expressed human SULT1A1*1, SULT1A1*2, SULT1B1, and SULT1E1 showed that triclosan inhibited the activities of each of these purified enzymes with IC50 concentrations between 2.09 and 7.5 muM. Triclosan was generally a less potent inhibitor of microsomal glucuronidation. IC50 concentrations for triclosan with 3-OH-BaP, acetaminophen, and bisphenol A as substrates were 4.55, 297, and >200 muM, respectively. Morphine glucuronidation was not inhibited by 50 muM triclosan. The kinetics of 3-OH-BaP sulfonation and glucuronidation were examined in the presence of varying concentrations of triclosan: the inhibition of sulfonation was noncompetitive, whereas that of glucuronidation was competitive. These findings reveal that the commonly used bactericide triclosan is a selective inhibitor of the glucuronidation and sulfonation of phenolic xenobiotics.