Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes inmice

Journal Article · Wed Oct 15 00:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.07.004· OSTI ID:21144151

Xia, Xiaojun; Sonoda, Junichiro ^[1]; Zhang, Jun ^[2]; Pontius, Elizabeth; Abey, Jane ^[3]; Evans, Ronald M ^[1]; Moore, David D ^[2]; DiGiovanni, John ^[3]

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1. Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, CA 92037 (United States)
2. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 (United States)
3. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Park Road 1-C, Smithville, TX 78957 (United States)

Cytochromes P450 (P450s) and glutathione S-transferases (GSTs) constitute two important enzyme families involved in carcinogen metabolism. Generally, P450s play activation or detoxifying roles while GSTs act primarily as detoxifying enzymes. We previously demonstrated that oral administration of the linear furanocoumarins, isopimpinellin and imperatorin, modulated P450 and GST activities in various tissues of mice. The purpose of the present study was to compare a broader range of naturally occurring coumarins (simple coumarins, and furanocoumarins of the linear and angular type) for their abilities to modulate hepatic drug-metabolizing enzymes when administered orally to mice. We now report that all of the different coumarins tested (coumarin, limettin, auraptene, angelicin, bergamottin, imperatorin and isopimpinellin) induced hepatic GST activities, whereas the linear furanocoumarins possessed the greatest abilities to induce hepatic P450 activities, in particular P450 2B and 3A. In both cases, this corresponded to an increase in protein expression of the enzymes. Induction of P4502B10, 3A11, and 2C9 by xenobiotics often is a result of activation of the pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR). Using a pregnane X receptor reporter system, our results demonstrated that isopimpinellin activated both PXR and its human ortholog SXR by recruiting coactivator SRC-1 in transfected cells. In CAR transfection assays, isopimpinellin counteracted the inhibitory effect of androstanol on full-length mCAR, a Gal4-mCAR ligand-binding domain fusion, and restored coactivator binding. Orally administered isopimpinellin induced hepatic mRNA expression of Cyp2b10, Cyp3a11, and GSTa in CAR(+/+) wild-type mice. In contrast, the induction of Cyp2b10 mRNA by isopimpinellin was attenuated in the CAR(-/-) mice, suggesting that isopimpinellin induces Cyp2b10 via the CAR receptor. Overall, the current data indicate that naturally occurring coumarins have diverse activities in terms of inducing various xenobiotic metabolizing enzymes based on their chemical structure.

• OSTI ID: 21144151
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 232; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTHRACENE
AUTOMOBILES
BENZENE
BENZOQUINONES
CARCINOGENS
COUMARIN
CYTOCHROMES
DIMETHYLBENZANTHRACENE
DME
ENZYME INDUCTION
GLUTATHIONE
HYDRATES
LIGANDS
LIVER
MICE
NAD
NITRIC OXIDE
NITROBENZENE
ORAL ADMINISTRATION
PHENOBARBITAL
PYRENE
RECEPTORS
STEROIDS
TRANSFERASES
XENOBIOTICS