Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family.
UDP-Glucuronosyltransferases (UGTs) conjugate a glucuronyl group from glucuronic acid to a wide range of lipophilic substrates to form a hydrophilic glucuronide conjugate. The glucuronide generally has decreased bioactivity and increased water solubility to facilitate excretion. Glucuronidation represents an important detoxification pathway for both endogenous waste products and xenobiotics, including drugs and harmful industrial chemicals. Two clinically significant families of UGT enzymes are present in mammals: UGT1s and UGT2s. Although the two families are distinct in gene structure, studies using recombinant enzymes have shown considerable overlap in their ability to glucuronidate many substrates, often obscuring the relative importance of the two families in the clearance of particular substrates in vivo. To address this limitation, we have generated a mouse line, termed ΔUgt2, in which the entire Ugt2 gene family, extending over 609 kilobase pairs, is excised. This mouse line provides a means to determine the contributions of the two UGT families in vivo. We demonstrate the utility of these animals by defining for the first time the in vivo contributions of the UGT1 and UGT2 families to glucuronidation of the environmental estrogenic agent bisphenol A (BPA). The highest activity toward this chemical is reported for human and rodent UGT2 enzymes. Surprisingly, our studies using the ΔUgt2 mice demonstrate that, while both UGT1 and UGT2 isoforms can conjugate BPA, clearance is largely dependent on UGT1s.
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
Matthew J
MJ
Fay
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
My Trang
MT
Nguyen
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
John N
JN
Snouwaert
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
Rebecca
R
Dye
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
Delores J
DJ
Grant
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.).
Wanda M
WM
Bodnar
Department of Genetics (M.J.F., M.T.N., J.N.S., R.D.), Department of Environmental Sciences and Engineering (W.M.B.), and Department of Medicine, Pulmonary and Critical Care Division (B.H.K.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Department of Biology and Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (D.J.G.) treawouns@aol.com.
Beverly H
BH
Koller
D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000172:deficiency* / Q000235:genetics*; D008658:Inactivation, Metabolic / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism* / Q000494:pharmacology; D000099148:UGT1A1 Enzyme; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D014453:Glucuronosyltransferase; D010636:Phenols; D015262:Xenobiotics; D000099148:UGT1A1 Enzyme; C006780:bisphenol A; D000098826:Bisphenol A Compounds