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Toxicol Lett. 2015 Feb 3;232(3):580-9. doi: 10.1016/j.toxlet.2014.12.015. Epub 2014 Dec 24.

Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR.

Author information

1
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL, United States; Auburn University Research Initiative in Cancer, Auburn University, Auburn, AL, United States. Electronic address: srp0010@auburn.edu.
2
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL, United States; Auburn University Research Initiative in Cancer, Auburn University, Auburn, AL, United States.
3
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL, United States.
4
Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, United States.
5
Department of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, AL, United States.
6
Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States.

Abstract

Activation of human pregnane X receptor (hPXR)-regulated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1) plays an important role in mediating adverse drug interactions. Given the common use of natural products as part of adjunct human health behavior, there is a growing concern about natural products for their potential to induce undesired drug interactions through the activation of hPXR-regulated CYP3A4 and MDR1. Here, we studied whether 3,3'-diindolylmethane (DIM), a natural health supplement, could induce hPXR-mediated regulation of CYP3A4 and MDR1 in human hepatocytes and intestinal cells. DIM, at its physiologically relevant concentrations, not only induced hPXR transactivation of CYP3A4 promoter activity but also induced gene expression of CYP3A4 and MDR1. DIM decreased intracellular accumulation of MDR1 substrate rhodamine 123, suggesting that DIM induces the functional expression of MDR1. Pharmacologic inhibition or genetic knockdown of hPXR resulted in attenuation of DIM induced CYP3A4 and MDR1 gene expression, suggesting that DIM induces CYP3A4 and MDR1 in an hPXR-dependent manner. Together, these results support our conclusion that DIM induces hPXR-regulated CYP3A4 and MDR1 gene expression. The inductive effects of DIM on CYP3A4 and MDR1 expression caution the use of DIM in conjunction with other medications metabolized and transported via CYP3A4 and MDR1, respectively.

KEYWORDS:

CYP3A4; Diindolylmethane; MDR1; PXR

PMID:
25542144
PMCID:
PMC4568078
DOI:
10.1016/j.toxlet.2014.12.015
[Indexed for MEDLINE]
Free PMC Article

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