Abstract

Glucuronide conjugation is a major route of drug metabolism and provides living organisms with a way to eliminate lipid-soluble chemicals to which they are exposed. Hepatic microsomal UDP-glucuronyltransferases (UDPGTs) catalyze the formation of glucuronides. Our laboratory has isolated a number of these proteins which are important in the conjugation of xenobiotics and endogenous substances. Determination of hepatic lobular localization and distribution of p-nitrophenol UDP-glucuronyltransferase (PNP-UDPGT), 17Beta-OH steroid UDPGT and 3Alpha-OH steroid UDPGT by immunohistochemical analyses is planned. Using specific antibodies, studies will demonstrate the changes in distribution produced by various agents such as 3-methylcholanthrene. In addition, liver, gastrointestinal tract, lung and kidney will be studied from Wistar rats possessing high levels of 3Alpha-OH steroid UDPGT (HA) and low levels of 3Alpha-OH steroid UDPGT (LA). These studies will allow for an understanding of the role of cellular heterogeneity in glucuronidation. Experiments will reveal N-terminal amino acid sequences of PNP-UDPGT, 17Beta-OH steroid UDPGT and 3Alpha-OH steroid UDPGT. In addition, the genetic regulation of expression of these transferases in untreated rat livers and in livers of rats treated with 3-methylcholanthrene will be studied. The mechanism of genetic variance for 3Alpha-OH steroid UDPGT will be studied in HA and LA Wistar rats. Purification of morphine and digitoxigenin monodigitoxoside UDPGTs will be performed and, then, these enzymes will be studied further as described for other UDPGTs. Purification and characterization of human liver UDPGTs will be performed. Experiments on phospholipid requirements, N-terminal amino acid sequences and the genetic regulation of expression of human liver UDPGTs are planned. Finally, the role of cellular heterogeneity in human tissues will be explored using immunohistochemical methods. Thus, how and where glucuronidation occurs can be probed and understood.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026221-10
Application #
3273719
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1979-04-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Coffman, Birgit L; Kearney, William R; Goldsmith, Shawn et al. (2003) Opioids bind to the amino acids 84 to 118 of UDP-glucuronosyltransferase UGT2B7. Mol Pharmacol 63:283-8
Rios, Gladys R; Tephly, Thomas R (2002) Inhibition and active sites of UDP-glucuronosyltransferases 2B7 and 1A1. Drug Metab Dispos 30:1364-7
Gestl, Shelley A; Green, Mitchell D; Shearer, Debra A et al. (2002) Expression of UGT2B7, a UDP-glucuronosyltransferase implicated in the metabolism of 4-hydroxyestrone and all-trans retinoic acid, in normal human breast parenchyma and in invasive and in situ breast cancers. Am J Pathol 160:1467-79
Coffman, B L; Kearney, W R; Green, M D et al. (2001) Analysis of opioid binding to UDP-glucuronosyltransferase 2B7 fusion proteins using nuclear magnetic resonance spectroscopy. Mol Pharmacol 59:1464-9
Barbier, O; Turgeon, D; Girard, C et al. (2000) 3'-azido-3'-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 28:497-502
Martinasevic, M K; Rios, G R; Miller, M W et al. (1999) Folate and folate-dependent enzymes associated with rat CNS development. Dev Neurosci 21:29-35
Cheng, Z; Radominska-Pandya, A; Tephly, T R (1999) Studies on the substrate specificity of human intestinal UDP- lucuronosyltransferases 1A8 and 1A10. Drug Metab Dispos 27:1165-70
King, C D; Rios, G R; Assouline, J A et al. (1999) Expression of UDP-glucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and identification of 5-hydroxytryptamine as a substrate. Arch Biochem Biophys 365:156-62
Gall, W E; Zawada, G; Mojarrabi, B et al. (1999) Differential glucuronidation of bile acids, androgens and estrogens by human UGT1A3 and 2B7. J Steroid Biochem Mol Biol 70:101-8
Cheng, Z; Rios, G R; King, C D et al. (1998) Glucuronidation of catechol estrogens by expressed human UDP-glucuronosyltransferases (UGTs) 1A1, 1A3, and 2B7. Toxicol Sci 45:52-7

Showing the most recent 10 out of 55 publications