title: Glucuronidation and excretion of nonylphenol in perfused rat liver.
abstract: Nonylphenol, an environmental estrogenic chemical, is reported to have adverse effects on the reproductive organs of animals. In this study, the metabolism of nonylphenol and that of other alkylphenols in the rat liver was investigated using liver perfusion. Alkylphenols (nonylphenol, hexylphenol, butylphenol, and ethylphenol) were glucuronidated by rat liver microsomes. Nonylphenol was found to be conjugated with glucuronic acid by an isoform of UDP-glucuronosyltransferase, UGT2B1, expressed in yeast AH22 cells. However, when nonylphenol was perfused into rat liver in situ, it was difficult for free nonylphenol and conjugated metabolite to be excreted into the bile or vein, and most of the perfused nonylphenol remained free and as a glucuronide conjugate in the liver tissue, even after 1 h of perfusion. After 1 h of perfusion of the other alkylphenols, most of them were excreted into the bile as glucuronides. Ethylphenol, which has the shortest alkyl chain, was excreted rapidly into both the bile and vein; however, the excretion rates of alkylphenols having longer alkyl chains tended to be slow. MRP-2-deficient Eisai hyperbilirubinemic rats could not secrete alkylphenol-glucuronides into the bile, indicating that alkylphenol-glucuronides are transported by MRP-2 to the bile in normal Sprague-Dawley rats. The results indicate that the kinetics of excretion of alkylphenol-glucuronides into the bile or vein depends on the length of alkyl chain and suggest that nonylphenol-glucuronide formed in the liver cannot be transported by MRP-2.
authors.affiliation: Department of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, 069-8501 Japan.
authors.forename: Tomo
authors.initials: T
authors.lastname: Daidoji
authors.forename: Hiroki
authors.initials: H
authors.lastname: Inoue
authors.forename: Seiyu
authors.initials: S
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yokota
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003135:Common Bile Duct; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006933:Hyperbilirubinemia, Hereditary / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology; D010477:Perfusion / Q000379:methods*; D010636:Phenols / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011169:Portal Vein; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
chemical_list: D020719:Glucuronides; D014453:Glucuronosyltransferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010636:Phenols; D014535:Uridine Diphosphate Glucuronic Acid; C025256:nonylphenol