Document Detail

Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination.
MedLine Citation:
PMID:  18098064     Owner:  NLM     Status:  MEDLINE    
The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor alpha (ERalpha) and pregnane X receptor (PXR) was examined by co-transfecting ERalpha- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.
H Jeong; S Choi; J W Song; H Chen; J H Fischer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Xenobiotica; the fate of foreign compounds in biological systems     Volume:  38     ISSN:  0049-8254     ISO Abbreviation:  Xenobiotica     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2007-12-21     Completed Date:  2008-04-30     Revised Date:  2014-03-28    
Medline Journal Info:
Nlm Unique ID:  1306665     Medline TA:  Xenobiotica     Country:  England    
Other Details:
Languages:  eng     Pagination:  62-75     Citation Subset:  IM    
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MeSH Terms
Antihypertensive Agents / metabolism*
Cells, Cultured
Dose-Response Relationship, Drug
Glucuronosyltransferase / genetics*,  metabolism*
Labetalol / metabolism*
Mass Spectrometry
Progesterone / pharmacology*
Promoter Regions, Genetic
Recombinant Proteins / genetics,  metabolism
Transcription, Genetic
Grant Support
Reg. No./Substance:
0/Antihypertensive Agents; 0/Recombinant Proteins; 4G7DS2Q64Y/Progesterone; EC 2.4.1.-/UGT1A1 enzyme; EC 2.4.1.-/UGT2B7 protein, human; EC; R5H8897N95/Labetalol

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