Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo
Poulton EJ, Levy L, Lampe JW, Shen DD, Tracy J, Shuhart MC, Thummel KE, Eaton DL
Toxicology and applied pharmacology · 37 citas
Cómo se estudió
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- Ensayo controlado aleatorizado (indexado por PubMed)
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Quién lo pagó
- Financiación
- Financiación independiente
- Universidad u hospital
- Johns Hopkins University
- Universidad u hospital
- Georgia Clinical and Translational Science Alliance
- Gobierno
- National Institutes of Health
- Gobierno
- U.S. Public Health Service
- Gobierno
- National Cancer Institute
- Gobierno
- National Institute of General Medical Sciences
- Gobierno
- National Institute of Environmental Health Sciences
- Gobierno
- National Center for Research Resources
- Gobierno
- NIGMS NIH HHS
- Gobierno
- NIEHS NIH HHS
- Gobierno
- PHS HHS
- Gobierno
- NCI NIH HHS
- Gobierno
- NCRR NIH HHS
- Subvenciones
- National Center for Research Resources (UL 1RR 025014); National Cancer Institute (T32-CA-080416); National Institute of General Medical Sciences (R01 GM 063666); National Institute of Environmental Health Sciences ([P30ES007033); National Institute of General Medical Sciences (P01GM032165); National Institute of General Medical Sciences (R01 GM079280-01A1); U.S. Public Health Service (T32ESO7032); National Institute of General Medical Sciences (R01 GM079280); National Institute of Environmental Health Sciences (T32ES007032)
Según 13 financiadores declarados.
Publicación
- Publicado
- 2012-11-12 · Toxicol Appl Pharmacol · vol. 266 · número 1 · págs. 122–131
- Editorial
- Elsevier BV
- Citado
- 40 citas · más que el 86% de estudios similares · 2.3× el promedio de su campo
- Referencias
- 52 trabajos
- Acceso
- Acceso abierto (copia en repositorio)
- Áreas de investigación
- Pharmacogenetics and Drug Metabolism · Drug Transport and Resistance Mechanisms · Genomics, phytochemicals, and oxidative stress
- Palabras clave
- sulforaphane, pregnane X receptor, CYP3A4 induction, drug-drug interactions, rifampicin, midazolam, broccoli sprout extract, xenobiotic metabolism
- MeSH
- animals, mice, inbred c57bl, mice, transgenic, humans, mice, brassica, thiocyanates, isothiocyanates, sulfoxides, receptors, steroid, plant extracts, treatment outcome, cross-over studies, adult, female, male, young adult, pregnane x receptor
8 autores
- Emma-Jane Poulton🇺🇸University of Washington
- Lisa Levy🇺🇸Fred Hutch Cancer Center
- Johanna W. Lampe🇺🇸University of Washington; Fred Hutch Cancer Center
- Danny D. Shen🇺🇸University of Washington
- Julia Helen Tracy🇺🇸University of Washington
- Margaret C. Shuhart
- Kenneth E. Thummel🇺🇸University of Washington
- David L. Eaton🇺🇸 · autor de correspondenciaUniversity of Washington
Resumen
El texto original del estudio, en el idioma en que se publicó.
Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand - rifampicin (300mg/d) was given alone for 7days in arm 1, or in daily combination with 450μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology.
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