Abstract
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 Km and Vmax values for triclosan sulfonation were 8.5 μM and 0.096 nmol/min/mg protein, whereas Km and Vmax values for glucuronidation were 107 μM 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 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 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.
Footnotes
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This work was supported by Grant P42-ES-07375 from the National Institute of Environmental Health Sciences, National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institute of Environmental Health Sciences, National Institutes of Health. A portion of this work was presented at the Society of Toxicology annual meeting, March 9-12, 2003.
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doi:10.1124/dmd.104.000273.
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ABBREVIATIONS: 3-OH-BaP, 3-hydroxy-benzo(a)pyrene; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; SULT, PAPS-sulfotransferase; TCA, trichloroacetic acid; TLC, thin-layer chromatography; UGT, UDP-glucuronosyltransferase; UDPGA, uridine diphosphoglucuronic acid.
- Received April 14, 2004.
- Accepted July 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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