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Received for publication April 15, 2004.
Revised July 9, 2004.
Accepted for publication July 12, 2004.
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 PAPS-sulfotransferases and UDP-glucuronosyltransferases, in human liver cytosol and microsomes. Triclosan was sulfonated and glucuronidated in human liver. The apparent Km and Vmax values for triclosan sulfonation were 8.5 µM and 0.096 nmol/min/mg protein, while Km and Vmax values for glucuronidation were 107 µM and 0.739 nmol/min/mg protein. Triclosan inhibited the hepatic cytosolic sulfonation of 3-OH-BaP, bisphenol A, p-nitrophenol and acetaminophen with IC50 concentrations of 2.87, 2.96, 6.45 and 17.8 µM 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 µM. 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 µM respectively. Morphine glucuronidation was not inhibited by 50 µM 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 non-competitive, while 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.
Key words:
drug interactions, environmental toxicology, enzyme inhibitors, glucuronidation, inhibition, phase II drug metabolism, sulfate conjugation, sulfotransferases, UDP glucuronyltransferases
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