Indirubin, a component of Ban-Lan-Gen, activates CYP3A4 gene transcription through the human pregnane X receptor

Takeshi Kumagai; Yusuke Aratsu; Ryosuke Sugawara; Takamitsu Sasaki; Shinichi Miyairi; Kiyoshi Nagata

doi:10.1016/j.dmpk.2016.01.002

Indirubin, a component of Ban-Lan-Gen, activates CYP3A4 gene transcription through the human pregnane X receptor

Drug Metab Pharmacokinet. 2016 Apr;31(2):139-45. doi: 10.1016/j.dmpk.2016.01.002. Epub 2016 Jan 22.

Authors

Takeshi Kumagai¹, Yusuke Aratsu², Ryosuke Sugawara³, Takamitsu Sasaki⁴, Shinichi Miyairi⁵, Kiyoshi Nagata³

Affiliations

¹ Department of Environmental Health Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan. Electronic address: ta-kuma@tohoku-pharm.ac.jp.
² Department of Environmental Health Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan; Drug Metabolism and Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
³ Department of Environmental Health Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
⁴ Department of Environmental Health Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan; Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
⁵ Laboratory of Organic Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashino, Funabashi, Chiba 274-8555, Japan.

PMID: 26987505
DOI: 10.1016/j.dmpk.2016.01.002

Abstract

Ban-Lan-Gen is the common name for the dried roots of indigo plants, including Polygonum tinctorium, Isatis indigotica, Isatis tinctoria, and Strobilanthes cusia. Ban-Lan-Gen is frequently used as an anti-inflammatory and an anti-viral for the treatment of hepatitis, influenza, and various types of inflammation. One of the cytochrome P450 (CYP) enzymes, CYP3A4, is responsible for the metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. In this study, we investigated the effect of Ban-Lan-Gen on the transcriptional activation of the CYP3A4 gene. Ban-Lan-Gen extract increased CYP3A4 gene reporter activity in a dose-dependent manner. Indirubin, one of the biologically active ingredients in the Ban-Lan-Gen, also dose-dependently increased CYP3A4 gene reporter activity. Expression of short hairpin RNA for the human pregnane X receptor (hPXR-shRNA) inhibited CYP3A4 gene reporter activity, and overexpression of human PXR increased indirubin- and rifampicin-induced CYP3A4 gene reporter activity. Furthermore, indirubin induced CYP3A4 mRNA expression in HepG2 cells. Taken together, these results indicate that indirubin, a component of Ban-Lan-Gen, activated CYP3A4 gene transcription through the activation of the human PXR.

Keywords: AhR activator; CYP3A4 induction; Herb–drug interactions; Indirubin; PXR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytochrome P-450 CYP3A / genetics*
Cytochrome P-450 CYP3A / metabolism
Dose-Response Relationship, Drug
Hep G2 Cells
Humans
Indoles / pharmacology
Pregnane X Receptor
RNA, Messenger / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Steroid / metabolism*
Structure-Activity Relationship
Transcriptional Activation / drug effects*
Transcriptional Activation / genetics

Substances

Indoles
Pregnane X Receptor
RNA, Messenger
Receptors, Steroid
Cytochrome P-450 CYP3A
CYP3A4 protein, human
indirubin