During pregnancy, it is ideal for pregnant women to avoid use of medications to protect the developing fetus from any potential adverse effects. But pre-existing medical conditions or disorders to which pregnant women are susceptible mandate continued use of medicines. This unavoidable drug treatment requires accurate pharmacokinetic information because under- or over-exposure may result in detrimental clinical outcomes not only in the mother but also in the fetus. Clinical studies in pregnant women have suggested that pharmacokinetic profiles of many drugs are altered during pregnancy. Generally, oral absorption of drugs is delayed, and distribution and renal excretion of drugs increase. Hepatic drug metabolism, on the other hand, has been suggested to change in a metabolic pathway-dependent manner in pregnancy. However, it is currently unclear whether the data reflect true changes in expression or function of hepatic drug metabolizing enzymes, apart from changes in other factors, such as changes in protein binding of a drug or blood flow to the liver. This necessitates an in vitro system where changes in hepatic drug metabolism can be exclusively examined. Physiological changes accompanying pregnancy are expected to be responsible for altered drug metabolism in pregnancy. The most pronounced change in pregnant women is a dramatic increase in the production of female hormones such as estrogen and progesterone. The elevated hormones may be responsible for altered hepatic drug metabolism in pregnancy. At the high concentrations attained in pregnancy, female hormones have functions different from their conventional role as gonadal hormones. Progesterone binds to and activates a transcriptional regulator pregnane xenobiotic receptor (PXR), which induces expression of major drug metabolizing enzymes including cytochrome P450 enzymes and UDP- glucuronosyltransferases (UGTs). Furthermore, estrogen promotes the expression of UGT1A4 and -1A9 in HepG2 cells, mediated via the action of estrogen receptor-? (ER?). Based on the evidence, we propose to test the hypothesis that the hormones elevated during pregnancy, estrogen and progesterone, globally modulate expression of hepatic drug metabolizing enzymes, leading to altered hepatic elimination of drugs. The following specific aims are designed accordingly. (1) Determine the enzyme-specific effects of estrogen and progesterone on hepatic drug metabolism. The functional significance of hormonal regulation will be investigated by examining how the hepatic elimination rates of various probe drugs change in human hepatocytes after treatment of the hepatocytes with female hormones. (2) Define the mechanisms by which estradiol regulates the expression of UGT1A4 and -1A9. Electrophoretic mobility shift assay, DNase I protection, and mutation assays will be performed. (3) Identify estradiol- or progesterone-responsive genes in the liver. Microarray experiments (Affymetrix Human Genome U133 plus 2.0 GeneChip array) will be performed using RNA samples prepared from human hepatocytes after hormone treatment.

Public Health Relevance

Medication use by pregnant women is common, but drug behaviors in this population are generally different from those in non-pregnant women or men. Understanding of these changes is important in determination of optimal dosing regimen. We propose to investigate mechanisms of such changes in drug behaviors. The knowledge obtained from this study can be expanded to optimize drug therapy in other groups of women, such as oral contraceptive users, thus benefiting women in general. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD055313-01A2
Application #
7529999
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Zajicek, Anne
Project Start
2008-07-20
Project End
2010-06-30
Budget Start
2008-07-20
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$191,223
Indirect Cost
Name
University of Illinois at Chicago
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Koh, Kwi Hye; Xie, Hui; Yu, Ai-Ming et al. (2011) Altered cytochrome P450 expression in mice during pregnancy. Drug Metab Dispos 39:165-9
Yang, Kyunghee; Koh, Kwi Hye; Jeong, Hyunyoung (2010) Induction of CYP2B6 and CYP3A4 expression by 1-aminobenzotriazole (ABT) in human hepatocytes. Drug Metab Lett 4:129-33
Jeong, Hyunyoung (2010) Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug Metab Toxicol 6:689-99
Chen, Huiqing; Yang, Kyunghee; Choi, Suyoung et al. (2009) Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol: a potential mechanism of increased lamotrigine elimination in pregnancy. Drug Metab Dispos 37:1841-7