Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus

被引:97
作者
Chen, SJ
Beaton, D
Nguyen, N
Senekeo-Effenberger, K
Brace-Sinnokrak, E
Argikar, U
Remmel, RP
Trottier, J
Barbier, O
Ritter, JK
Tukey, RH
机构
[1] Univ Calif San Diego, Dept Pharmacol, Lab Environm Toxicol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[3] Univ Laval, Fac Pharm, Quebec City, PQ G1K 7P4, Canada
[4] Univ Laval, Ctr Hosp Univ Laval Res Ctr, Mol Endocrinol & Oncol Res Ctr, Quebec City, PQ G1K 7P4, Canada
[5] Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA
[6] Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA
关键词
D O I
10.1074/jbc.M506683200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The human UDP-glucuronosyltransferase1(UGT1) locus spans nearly 200 kb on chromosome 2 and encodes nine UGT1A proteins that play a prominent role in drug and xenobiotic metabolism. Transgenic UGT1 (Tg-UGT1) mice have been created, and it has been demonstrated that tissue-specific and xenobiotic receptor control of the UGT1A genes is influenced through circulating humoral factors. In Tg-UGT1 mice, the UGT1A proteins are differentially expressed in the liver and gastrointestinal tract. Gene expression profiles confirmed that all of the UGT1A genes can be targeted for regulation by the pregnane X receptor activator pregnenolone-16 alpha-carbonitrile (PCN) or the Ah receptor ligand 2,3,7,8-tetrachlorodibenzop- dioxin ( TCDD). In addition, the selective induction of glucuronidation activity toward lamotrigine, ethinyl estradiol, chenodeoxycholic acid, and lithocholic acid by either PCN or TCDD in small intestine from Tg-UGT1 mice corresponded to expression of the locus in this tissue. Induction of UGT1A1 by PCN and TCDD is believed to be highly dependent upon glucocorticoids, because submicromolar concentrations of dexamethasone actively promote PCN and TCDD induction of UGT1A1 in Tg-UGT1 primary hepatocytes. The role of hormonal control of the UGT1 locus was further verified in pregnant and nursing Tg-UGT1 mice. Inmaternal 14-daypost-conception Tg-UGT1mice, liver UGT1A1, UGT1A4, and UGT1A6 were induced, with the levels returning to near normal by birth. However, maternal liver UGT1A4 and UGT1A6 were dramatically elevated and maintained after birth, indicating that these proteins may play a critical role in maternal metabolism during lactation. With expression of the UGT1 locus confirmed in a variety of mouse tissues, these results suggested that the Tg-UGT1 mice will be a useful model to examine the regulatory and functional properties of human glucuronidation.
引用
收藏
页码:37547 / 37557
页数:11
相关论文
共 50 条
[1]   The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor α and γ target gene [J].
Barbier, O ;
Villeneuve, L ;
Bocher, V ;
Fontaine, C ;
Torra, IP ;
Duhem, C ;
Kosykh, V ;
Fruchart, JC ;
Guillemette, C ;
Staels, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (16) :13975-13983
[2]   AH receptor-controlled transcriptional regulation and function of rat and human UDP-glucuronosyltransferase isoforms [J].
Bock, KW ;
Gschaidmeier, H ;
Heel, H ;
Lehmkoster, T ;
Munzel, PA ;
Raschko, F ;
Bock-Hennig, B .
ADVANCES IN ENZYME REGULATION, VOL 38, 1998, 38 :207-222
[3]   Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms [J].
Court, MH ;
Greenblatt, DJ .
PHARMACOGENETICS, 2000, 10 (04) :355-369
[4]  
Dutton GJ, 1980, GLUCURONIDATION DRUG
[5]  
EBNER T, 1993, MOL PHARMACOL, V43, P649
[6]   Differential glucuronidation of bile acids, androgens and estrogens by human UGT1A3 and 2B7 [J].
Gall, WE ;
Zawada, G ;
Mojarrabi, B ;
Tephly, TR ;
Green, MD ;
Coffman, BL ;
Mackenzie, PI ;
Radominska-Pandya, A .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1999, 70 (1-3) :101-108
[7]   Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression [J].
Gardner-Stephen, D ;
Heydel, JM ;
Goyal, A ;
Lu, Y ;
Xie, W ;
Lindblom, T ;
Mackenzie, P ;
Radominska-Pandya, A .
DRUG METABOLISM AND DISPOSITION, 2004, 32 (03) :340-347
[8]   Lamotrigine in pregnancy and lactation [J].
Gentile, S .
ARCHIVES OF WOMENS MENTAL HEALTH, 2005, 8 (01) :57-58
[9]   Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus [J].
Gong, QH ;
Cho, JW ;
Huang, T ;
Potter, C ;
Gholami, N ;
Basu, NK ;
Kubota, S ;
Carvalho, S ;
Pennington, MW ;
Owens, IS ;
Popescu, NC .
PHARMACOGENETICS, 2001, 11 (04) :357-368
[10]   Expression of the human CYP3A4 gene in the small intestine of transgenic mice:: In vitro metabolism and pharmacokinetics of midazolam [J].
Granvil, CP ;
Yu, AM ;
Elizondo, G ;
Akiyama, TE ;
Cheung, C ;
Feigenbaum, L ;
Krausz, KW ;
Gonzalez, FJ .
DRUG METABOLISM AND DISPOSITION, 2003, 31 (05) :548-558