title: Formation of a structurally novel, serial diglucuronide of 4-hydroxybiphenyl by further glucuronidation of a monoglucuronide in dog liver microsomes.
abstract: Incubation of 4-hydroxybiphenyl (p-phenylphenol) in the presence of UDP-glucuronic acid (UDPGA) with liver microsomes from male and female dogs produced a more polar metabolite peak than a simultaneously produced peak of 4-hydroxybiphenyl monoglucuronide in the high performance liquid chromatography (HPLC) chromatogram. Tandem mass spectrometry (MS/MS) and two-dimensional nuclear magnetic resonance (NMR) analyses revealed this polar metabolite as a 4-hydroxybiphenyl diglucuronide having a beta-D-glucuronopyranosyl-(1-->2)-beta-D-glucuronopyranosyl moiety, where the two glucuronic acids are connected directly at the 1''-->2' position. Liver microsomes from Sprague-Dawley rat, cynomolgus monkey and human, converted 4-hydroxybiphenyl only to the monoglucuronide, suggesting that there is a dog UDP-glucuronosyltransferase (UGT), with a wider substrate specificity capable of glucuronidating 4-hydroxybiphenyl monoglucuronide to the diglucuronide.
authors.affiliation: Pharmacokinetics and Drug Delivery Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. tmurai@shina.sankyo.co.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murai
authors.forename: Fujiko
authors.initials: F
authors.lastname: Tsuruta
authors.forename: Toshio
authors.initials: T
authors.lastname: Terao
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Haruo
authors.initials: H
authors.lastname: Iwabuchi