CYP3A4 is the major P450 present in human liver and small bowel? epithelial cells (enterocytes). The contribution of enterocyte CYP3A4? to drug elimination is believed to be substantial. However,? distinguishing the contributions of the intestinal vs. the liver enzyme,? as well as the role of the transporter P-glycoprotein, has been? problematic. We have developed experimental techniques that have? enabled us to safely study liver and enterocyte CYP3A4 in living people.? We have shown that there exists marked inter- and intraindividual? variation in the activity of enterocyte CYP3A4. We have also shown that? there is generally not a good intraindividual correlation between the? relative activities of CYP3A4 in liver and intestine. To further? investigate the mechanisms underlying these variations, we have chosen? to intensively pursue our observation that some fruit juices (grapefruit? juice and Seville orange juice) cause a marked and relatively rapid loss? of enterocyte CYP3A4 by a mechanism that does not appear to involve loss? of CYP3A4 mRNA. We have shown that 2 juice-derived furanocoumarins (FC? s), 6',7'-dihydroxybergamottin (DHB) and a related dimer (FC726), cause? selective loss of CYP3A4 in a novel human intestinal (Caco-2) cell? monolayer culture system, and that DHB is a mechanism-based inactivator? of CYP3A4. However, DHB and FC726 can not fully account for the effects? of whole juice, and their effects may not be CYP3A4 selective. We will? test the hypothesis that multiple FC s, which are quite ubiquitous in? fruits and vegetables, cause mechanism-based inactivation and? accelerated intracellular degradation of CYP3A4. To this end, we will? characterize the time course of the effects of selected FC s on CYP3A4? and on other major enterocyte P450s in human intestinal microsomes, in? our Caco-2 cell system, and in healthy volunteers. We will also? determine the effects of selected FC s on rates of synthesis and? degradation of CYP3A4 in our cultured cells. Finally, we will test the? hypothesis that some oral medication regimens that result in clinically? important induction of CYP3A4 in liver do not induce the enzyme in? enterocytes. The data obtained from the proposed studies should provide? substantial insight into the basis for variations in CYP3A4 activity? between people, within a person over time, and between liver and? intestine. In addition, the identification of orally administered FC? s that specifically ablate CYP3A4 activity in enterocytes (but not? liver), or drugs that selectively induce CYP3A4 in liver (but not in? enterocytes) would provide powerful research tools to assess the? relative contributions of enterocyte and hepatic CYP3A4 to the? disposition of xenobiotics in living people.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Okita, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
Zip Code
Bushel, P R; Fannin, R D; Gerrish, K et al. (2017) Blood gene expression profiling of an early acetaminophen response. Pharmacogenomics J 17:230-236
Fannin, R D; Gerrish, K; Sieber, S O et al. (2016) Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther 99:432-41
Jeffries, Rex E; Gamcsik, Michael P; Keshari, Kayvan R et al. (2013) Effect of oxygen concentration on viability and metabolism in a fluidized-bed bioartificial liver using ³¹P and ¹³C NMR spectroscopy. Tissue Eng Part C Methods 19:93-100
Jeffries, Rex E; Macdonald, Jeffrey M (2012) New advances in MR-compatible bioartificial liver. NMR Biomed 25:427-42
Fannin, Rick D; Russo, Mark; O'Connell, Thomas M et al. (2010) Acetaminophen dosing of humans results in blood transcriptome and metabolome changes consistent with impaired oxidative phosphorylation. Hepatology 51:227-36
Harrill, Alison H; Watkins, Paul B; Su, Stephen et al. (2009) Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res 19:1507-15
Leslie, Elaine M; Watkins, Paul B; Kim, Richard B et al. (2007) Differential inhibition of rat and human Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1)by bosentan: a mechanism for species differences in hepatotoxicity. J Pharmacol Exp Ther 321:1170-8
Zhou, Changcheng; Assem, Mahfoud; Tay, Jessica C et al. (2006) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J Clin Invest 116:1703-12
Lamba, Jatinder K; Chen, Xin; Lan, Lu-Bin et al. (2006) Increased CYP3A4 copy number in TONG/HCC cells but not in DNA from other humans. Pharmacogenet Genomics 16:415-27
Paine, Mary F; Widmer, Wilbur W; Hart, Heather L et al. (2006) A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr 83:1097-105

Showing the most recent 10 out of 50 publications