Bioavailability of the diterpenoid 14-deoxy-11,12-didehydroandrographolide in rats and up-regulation of hepatic drug-metabolizing enzyme and drug transporter expression

Chih-Ching Yen; Yun-Ta Liu; Ying-Jyan Lin; Ya-Chen Yang; Chien-Chih Chen; Hsien-Tsung Yao; Haw-Wen Chen; Chong-Kuei Lii

doi:10.1016/j.phymed.2019.152841

Bioavailability of the diterpenoid 14-deoxy-11,12-didehydroandrographolide in rats and up-regulation of hepatic drug-metabolizing enzyme and drug transporter expression

Phytomedicine. 2019 Aug:61:152841. doi: 10.1016/j.phymed.2019.152841. Epub 2019 Jan 24.

Authors

Chih-Ching Yen¹, Yun-Ta Liu², Ying-Jyan Lin², Ya-Chen Yang³, Chien-Chih Chen⁴, Hsien-Tsung Yao², Haw-Wen Chen⁵, Chong-Kuei Lii⁶

Affiliations

¹ Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan; Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
² Department of Nutrition, China Medical University, Taichung 404, Taiwan.
³ Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan.
⁴ Department of Cosmetic Science, Chang Gung University of Science and Technology, Kweishan, Taoyuan 333, Taiwan.
⁵ Department of Nutrition, China Medical University, Taichung 404, Taiwan. Electronic address: chenhw@mail.cmu.edu.tw.
⁶ Department of Nutrition, China Medical University, Taichung 404, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: cklii@mail.cmu.edu.tw.

PMID: 31035043
DOI: 10.1016/j.phymed.2019.152841

Abstract

Background: 14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated.

Purpose: In this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability.

Study design: deAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes.

Results: After a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (C_max), time to reach the C_max, area under the curve (AUC_0-24h), mean retention time, and half-life (t_1/2) of deAND were 2.65 ± 0.68 μg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 μg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 μM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively.

Conclusion: These results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.

Keywords: 14-Deoxy-11,12-didehydroandrographolide; Bioavailability; Drug transporters; Drug-metabolizing enzymes; Transcription factors.

MeSH terms

Administration, Oral
Andrographis / chemistry
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Biological Availability
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism
Diterpenes / administration & dosage
Diterpenes / blood
Diterpenes / pharmacokinetics*
Enzymes / genetics
Enzymes / metabolism*
Glucuronosyltransferase / genetics
Glucuronosyltransferase / metabolism
Hepatocytes / drug effects*
Hepatocytes / physiology
Inactivation, Metabolic / drug effects
Liver / drug effects
Liver / enzymology
Liver / metabolism
Male
NAD(P)H Dehydrogenase (Quinone) / genetics
NAD(P)H Dehydrogenase (Quinone) / metabolism
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism
Organic Anion Transporters / genetics
Organic Anion Transporters / metabolism
Rats, Sprague-Dawley
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism
Up-Regulation / drug effects

Substances

14-deoxy-11,12-didehydroandrographolide
Ahr protein, rat
Basic Helix-Loop-Helix Transcription Factors
Diterpenes
Enzymes
NF-E2-Related Factor 2
Nfe2l2 protein, rat
Organic Anion Transporters
Receptors, Aryl Hydrocarbon
Ugt1a1 protein, rat
Cytochrome P-450 Enzyme System
NAD(P)H Dehydrogenase (Quinone)
NQO1 protein, rat
Glucuronosyltransferase