PT  - JOURNAL ARTICLE
AU  - Li-Quan Wang
AU  - Charles N. Falany
AU  - Margaret O. James
TI  - TRICLOSAN AS A SUBSTRATE AND INHIBITOR OF 3′-PHOSPHOADENOSINE 5′-PHOSPHOSULFATE-SULFOTRANSFERASE AND UDP-GLUCURONOSYL TRANSFERASE IN HUMAN LIVER FRACTIONS
AID  - 10.1124/dmd.104.000273
DP  - 2004 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1162--1169
VI  - 32
IP  - 10
4099  - http://dmd.aspetjournals.org/content/32/10/1162.short
4100  - http://dmd.aspetjournals.org/content/32/10/1162.full
SO  - Drug Metab Dispos2004 Oct 01; 32
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics