PMID- 35843411 OWN - NLM STAT- MEDLINE DCOM- 20220816 LR - 20220816 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 297 DP - 2022 Oct 28 TI - Homeostatic regulation of the aryl hydrocarbon receptor-cytochrome P450 1a axis by Scutellaria baicalensis-Coptis chinensis herb pair and its main constituents. PG - 115545 LID - S0378-8741(22)00584-0 [pii] LID - 10.1016/j.jep.2022.115545 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis (SB) and Coptis chinensis (CC) are widely used traditional Chinese medicine (TCM) for "heat-clearing and damp-drying" and "purging fire and detoxifying". SB-CC are commonly used as a herbal pair for synergistic treatment of various diseases such as bacteria-related infections, metabolic syndromes, and some inflammatory disorders. This herbal pair is commonly used in many famous TCM formula, like Huang-Lian-Jie-Du, Gegen-Qinlian, Banxia Xiexin decoction. Aryl hydrocarbon receptor (AHR) plays an essential role in the disposition of both xenobiotics and endogenous substances through the induction of cytochrome P450 1A (CYP1A) enzymes. Regulation of the AHR-CYP1A axis is increasingly implicated in drug-drug and drug-herb interactions. Research on SB-CC for regulatory effect on the AHR-CYP1A axis is only limited to few compounds. AIM OF THE STUDY: This study aimed to systematically investigate the regulatory effect of SB-CC and its main constitutes on the AHR-CYP1A axis in vitro and in vivo. MATERIALS AND METHODS: The livers of mice treated with SB-CC extract were subjected to RNA-sequencing (RNA-seq). The key target genes related to drug metabolism were screened, and the differential expression genes (DEGs) were validated by qRT-PCR, Western blot, and enzyme activity assay. Luciferase reporter gene, qRT-PCR, and Western blot assays were used to determine whether SB-CC and their main constituents could activate AHR and regulate CYP1A expression in HepG2 cells. The effect of SB-CC on the pharmacokinetics of phenacetin, a CYP1A substrate, were further observed in mice to test the net effect of SB-CC on CYP1A functions. The potential CYP1A inhibitors in SB-CC were screened and their inhibitory mechanisms were also studied using human liver microsomes. RESULTS: AHR and drug metabolism system, especially CYP1A1 and CYP1A2, were strongly affected in the liver of SB-CC-treated mice. These results were further validated by the findings that SB-CC increased CYP1A's mRNA, protein expression and activity in mouse liver. In HepG2 cells, SB, CC, baicalin, baicalein, chrysin, oroxylin A, berberine, coptisine and epiberberine increased CYP1A1 mRNA expression in an AHR-dependent way. Interestingly, SB-CC treatment for 14 days only slightly increased the systemic exposure of paracetamol in mice. In the CYP1A inhibition assay, SB, CC, baicalin, baicalein, wogonoside, wogonin, chrysin, oroxylin A, scutellarein, columbamine, coptisine, palmatine, epiberberine, and berberrubine inhibited CYP1A activity in different degree. CONCLUSIONS: These results suggested that SB-CC exerted dual regulatory effect on the AHR-CYP1A axis by increasing CYP1A expression but simultaneously inhibiting CYP1A activity, which may contribute to a tight modulation of AHR signaling for homeostatic control. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Song, Mengmeng AU - Song M AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: 20190433@njucm.edu.cn. FAU - Sheng, Xianjie AU - Sheng X AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: 20200700@njucm.edu.cn. FAU - Zhang, Jianrong AU - Zhang J AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: 20210627@njucm.edu.cn. FAU - Li, Xinru AU - Li X AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: 20210803@njucm.edu.cn. FAU - Dai, Qianyun AU - Dai Q AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: 20200547@njucm.edu.cn. FAU - Chen, Yan AU - Chen Y AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. FAU - Kang, An AU - Kang A AD - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: kanga@njucm.edu.cn. LA - eng PT - Journal Article DEP - 20220715 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Plant Extracts) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Aryl Hydrocarbon) RN - EC 1.14.14.1 (Cytochrome P-450 CYP1A1) SB - IM MH - Animals MH - Coptis chinensis MH - Cytochrome P-450 CYP1A1/genetics MH - Humans MH - Mice MH - Plant Extracts MH - RNA, Messenger MH - *Receptors, Aryl Hydrocarbon/genetics/metabolism MH - *Scutellaria baicalensis/chemistry OTO - NOTNLM OT - Aryl hydrocarbon receptor OT - CYP1A OT - Coptis chinensis OT - Scutellaria baicalensis EDAT- 2022/07/18 06:00 MHDA- 2022/08/17 06:00 CRDT- 2022/07/17 19:25 PHST- 2022/05/21 00:00 [received] PHST- 2022/06/30 00:00 [revised] PHST- 2022/07/11 00:00 [accepted] PHST- 2022/07/18 06:00 [pubmed] PHST- 2022/08/17 06:00 [medline] PHST- 2022/07/17 19:25 [entrez] AID - S0378-8741(22)00584-0 [pii] AID - 10.1016/j.jep.2022.115545 [doi] PST - ppublish SO - J Ethnopharmacol. 2022 Oct 28;297:115545. doi: 10.1016/j.jep.2022.115545. Epub 2022 Jul 15.