A Novel System for Evaluating the Inhibition Effect of Drugs on Cytochrome P450 Enzymes Based on Human-Induced Hepatocytes (hiHeps)

Overview

Journal Front Pharmacol

Date 2021 Nov 15

PMID 34776966

Citations 2

Authors

Yan Li

Ying-Yuan Lu

Jun Jia

Meng Fang

Lin Zhao

Yong Jiang

Yan Shi

Peng-Fei Tu

Xiao-Yu Guo

Affiliations

Soon will be listed here.

Abstract

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes . Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 based on hiHeps. Curcumin can inhibit many CYP enzymes , and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system . Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS-SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated . The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes , which has broad application prospects in drug research.

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References

Darnell M, Schreiter T, Zeilinger K, Urbaniak T, Soderdahl T, Rossberg I . Cytochrome P450-dependent metabolism in HepaRG cells cultured in a dynamic three-dimensional bioreactor. Drug Metab Dispos. 2011; 39(7):1131-8. DOI: 10.1124/dmd.110.037721. View

Akamine Y, Yasui-Furukori N, Uno T . Drug-Drug Interactions of P-gp Substrates Unrelated to CYP Metabolism. Curr Drug Metab. 2018; 20(2):124-129. DOI: 10.2174/1389200219666181003142036. View

Sudsakorn S, Bahadduri P, Fretland J, Lu C . 2020 FDA Drug-drug Interaction Guidance: A Comparison Analysis and Action Plan by Pharmaceutical Industrial Scientists. Curr Drug Metab. 2020; 21(6):403-426. DOI: 10.2174/1389200221666200620210522. View

Hu Z, Yang J, Cheng C, Huang Y, Du F, Wang F . Combinatorial metabolism notably affects human systemic exposure to ginsenosides from orally administered extract of Panax notoginseng roots (Sanqi). Drug Metab Dispos. 2013; 41(7):1457-69. DOI: 10.1124/dmd.113.051391. View

Meng Y, Du Z, Li Y, Wang L, Gao P, Gao X . Integration of Metabolomics With Pharmacodynamics to Elucidate the Anti-myocardial Ischemia Effects of Combination of Notoginseng Total Saponins and Safflower Total Flavonoids. Front Pharmacol. 2018; 9:667. PMC: 6026671. DOI: 10.3389/fphar.2018.00667. View

Chen J, Guo X, Lu Y, Shi M, Mu H, Qian Y . Large Volume Direct Injection Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Comparative Pharmacokinetic Study between Single and Combinatory Uses of Extract and Notoginseng Total Saponins. Pharmaceutics. 2020; 12(2). PMC: 7076352. DOI: 10.3390/pharmaceutics12020180. View

Schink M, Dehus O . Effects of mistletoe products on pharmacokinetic drug turnover by inhibition and induction of cytochrome P450 activities. BMC Complement Altern Med. 2017; 17(1):521. PMC: 5715639. DOI: 10.1186/s12906-017-2028-1. View

Hakkola J, Hukkanen J, Turpeinen M, Pelkonen O . Inhibition and induction of CYP enzymes in humans: an update. Arch Toxicol. 2020; 94(11):3671-3722. PMC: 7603454. DOI: 10.1007/s00204-020-02936-7. View

Thiengsusuk A, Boonprasert K, Na-Bangchang K . A Systematic Review of Drug Metabolism Studies of Plants With Anticancer Properties: Approaches Applied and Limitations. Eur J Drug Metab Pharmacokinet. 2019; 45(2):173-225. DOI: 10.1007/s13318-019-00582-8. View

10.

Cui H, Zhang Q, Wang J, Chen J, Zhang Y, Tong X . In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells. J Ethnopharmacol. 2014; 158 Pt A:388-96. DOI: 10.1016/j.jep.2014.10.018. View

11.

Du Y, Wang J, Jia J, Song N, Xiang C, Xu J . Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell. 2014; 14(3):394-403. DOI: 10.1016/j.stem.2014.01.008. View

12.

Zeilinger K, Freyer N, Damm G, Seehofer D, Knospel F . Cell sources for in vitro human liver cell culture models. Exp Biol Med (Maywood). 2016; 241(15):1684-98. PMC: 4999620. DOI: 10.1177/1535370216657448. View

13.

Underhill G, Khetani S . Advances in Engineered Human Liver Platforms for Drug Metabolism Studies. Drug Metab Dispos. 2018; 46(11):1626-1637. PMC: 6199629. DOI: 10.1124/dmd.118.083295. View

14.

Kong R, Ma J, Hwang S, Moon Y, Welch E, Weetall M . In vitro metabolism, reaction phenotyping, enzyme kinetics, CYP inhibition and induction potential of ataluren. Pharmacol Res Perspect. 2020; 8(2):e00576. PMC: 7083565. DOI: 10.1002/prp2.576. View

15.

Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z . Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell. 2014; 14(3):370-84. DOI: 10.1016/j.stem.2014.01.003. View

16.

Mann H . Drug-associated disease: cytochrome P450 interactions. Crit Care Clin. 2006; 22(2):329-45, vii. DOI: 10.1016/j.ccc.2006.02.004. View

17.

Williams J, Hyland R, Jones B, Smith D, Hurst S, Goosen T . Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004; 32(11):1201-8. DOI: 10.1124/dmd.104.000794. View

18.

Yu J, Petrie I, Levy R, Ragueneau-Majlessi I . Mechanisms and Clinical Significance of Pharmacokinetic-Based Drug-Drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017. Drug Metab Dispos. 2018; 47(2):135-144. DOI: 10.1124/dmd.118.084905. View

19.

Cheng H, Lu Y, Wang X, Ren H, Li Q, Wang S . Interaction between 3,4‑dichlorophenyl‑propenoyl‑sec.‑butylamine (3,4‑DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro. Eur J Pharm Sci. 2018; 123:241-248. DOI: 10.1016/j.ejps.2018.07.018. View

20.

Inoue T, Iwazaki N, Araki T, Hitotsumachi H . Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals. Curr Pharm Biotechnol. 2020; 21(9):773-779. DOI: 10.2174/1389201021666200131123524. View