PMID- 32563148 OWN - NLM STAT- MEDLINE DCOM- 20210301 LR - 20211204 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 129 DP - 2020 Sep TI - Catalpol coordinately regulates phase I and II detoxification enzymes of Triptolide through CAR and NRF2 pathways to reduce Triptolide-induced hepatotoxicity. PG - 110379 LID - S0753-3322(20)30572-2 [pii] LID - 10.1016/j.biopha.2020.110379 [doi] AB - Triptolide (TP), as the main component of Tripterygium Wilfordii (TW), can induce obvious liver injury when exerting the therapeutic effect. However, in our previous study, Catalpol (CAT), the main active ingredient of Rehmannia Glutinosa (RG), was shown to increase the drug clearance rate of TP and to attenuate TP-induced hepatotoxicity. Thus the present study aims to address the roles of phase I and II metabolic enzymes and the nuclear receptors in the detoxification process of TP, to analyze the mechanism of CAT reducing hepatotoxicity. For this purpose, SD rats and human liver cell line L-02 and HepG2 cells were selected, and treated with TP or the combination of TP and CAT in our study. Then the effect of CAT on detoxification of TP was analyzed, and the roles of phase I metabolic enzymes cytochrome P450 3A2/4 (CYP3A2/4) and phase II metabolic enzyme UDP-glucuronosyltransferase 1A6 (UGT1A6) and their related nuclear receptor regulations were evaluated. It was found that TP inhibited the transcription of CYP3A2/4. And through the constitutive androstane receptor (CAR) pathway, CAT not only significantly changed this inhibition and increased the expression of CYP3A2/4 but also increased the expression of CYP2C9, both of which are phase I detoxification enzymes of TP. And with the gene-silenced experiment, it was confirmed that this regulation was CAR-dependent. We also found that CAT could continue to exert a certain protective effect after CAR was silenced, with UGT1A6, the phase II detoxification enzyme of TP, significantly induced. And this was closely related to the enhanced transcriptional regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway. In conclusion, our results reveal that CAT can induce TP's phase I detoxification enzymes CYP3A2/4 and CYP2C9 through the CAR pathway, and induce TP's phase II detoxification enzyme UGT1A6 via the NRF2 pathway when CAR is strongly inhibited. And this coordinate regulation of CAT may be an important source of the effect for CAT to increase TP metabolic conversion and reduce TP hepatotoxicity. CI - Copyright (c) 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Fu, Ling AU - Fu L AD - The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. FAU - Zhou, Lingling AU - Zhou L AD - Jiangsu Provincial Key Laboratory of Pharmacology and Safety Evaluation of Material Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. FAU - Geng, Shan AU - Geng S AD - Jiangsu Provincial Key Laboratory of Pharmacology and Safety Evaluation of Material Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Sichuan Kelun Pharmaceutical CO., LTD., Chengdu 610071, China. FAU - Li, Ming AU - Li M AD - The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. FAU - Lu, Wei AU - Lu W AD - Jiangsu Provincial Key Laboratory of Pharmacology and Safety Evaluation of Material Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. FAU - Lu, Yan AU - Lu Y AD - The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210001, China. FAU - Feng, Zhe AU - Feng Z AD - The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: 260583@njucm.edu.cn. FAU - Zhou, Xueping AU - Zhou X AD - The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: zxp_njucm@163.com. LA - eng PT - Journal Article DEP - 20200617 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Constitutive Androstane Receptor) RN - 0 (Diterpenes) RN - 0 (Epoxy Compounds) RN - 0 (Iridoid Glucosides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - 0 (Nfe2l2 protein, rat) RN - 0 (Phenanthrenes) RN - 0 (Receptors, Cytoplasmic and Nuclear) RN - 19ALD1S53J (triptolide) RN - 2415-24-9 (catalpol) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A6) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - EC 2.4.1.17 (UDP-glucuronosyltransferase, UGT1A7) SB - IM MH - Animals MH - Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention & control MH - Constitutive Androstane Receptor MH - Cytochrome P-450 Enzyme System/genetics/*metabolism MH - Disease Models, Animal MH - Diterpenes/*metabolism MH - Epoxy Compounds/metabolism MH - Female MH - Glucuronosyltransferase/genetics/*metabolism MH - Hep G2 Cells MH - Hepatocytes/*drug effects/metabolism/pathology MH - Humans MH - Iridoid Glucosides/*pharmacology MH - Liver/*drug effects/enzymology/pathology MH - Metabolic Detoxication, Phase I MH - Metabolic Detoxication, Phase II MH - NF-E2-Related Factor 2/genetics/*metabolism MH - Phenanthrenes/*metabolism MH - Rats, Sprague-Dawley MH - Receptors, Cytoplasmic and Nuclear/genetics/*metabolism MH - Signal Transduction OTO - NOTNLM OT - CAR OT - Catalpol OT - Liver injury OT - Metabolic enzymes OT - NRF2 OT - Triptolide EDAT- 2020/06/21 06:00 MHDA- 2021/03/02 06:00 CRDT- 2020/06/21 06:00 PHST- 2020/02/12 00:00 [received] PHST- 2020/06/03 00:00 [revised] PHST- 2020/06/07 00:00 [accepted] PHST- 2020/06/21 06:00 [pubmed] PHST- 2021/03/02 06:00 [medline] PHST- 2020/06/21 06:00 [entrez] AID - S0753-3322(20)30572-2 [pii] AID - 10.1016/j.biopha.2020.110379 [doi] PST - ppublish SO - Biomed Pharmacother. 2020 Sep;129:110379. doi: 10.1016/j.biopha.2020.110379. Epub 2020 Jun 17.