Inhibitory Effect of Lygodium Root on the Cytochrome P450 3A Enzyme in vitro and in vivo

Abstract Objectives Glucosamine, chondroitin and diacerein are natural compounds commonly used in treating osteoarthritis. Their concomitant intake may trigger drug–natural product interactions. Cytochrome P450 (CYP) has been implicated in such interactions. Cytochrome P450 2D6 (CYP2D6) is a major hepatic CYP involved in metabolism of 25% of the clinical drugs. This study aimed to investigate the inhibitory effect of these antiarthritic compounds on CYP2D6. Methods CYP2D6 was heterologously expressed in Escherichia coli. CYP2D6–antiarthritic compound interactions were studied using in vitro enzyme kinetics assay and molecular docking. Results The high-performance liquid chromatography (HPLC)-based dextromethorphan O-demethylase assay was established as CYP2D6 marker. All glucosamines and chondroitins weakly inhibited CYP2D6 (IC50 values >300 µM). Diacerein exhibited moderate inhibition with IC50 and K i values of 34.99 and 38.27 µM, respectively. Its major metabolite, rhein displayed stronger inhibition potencies (IC50=26.22 μM and K i =32.27 μM). Both compounds exhibited mixed-mode of inhibition. In silico molecular dockings further supported data from the in vitro study. From in vitro–in vivo extrapolation, rhein presented an area under the plasma concentration-time curve (AUC) ratio of 1.5, indicating low potential to cause in vivo inhibition. Conclusions Glucosamine, chondroitin and diacerein unlikely cause clinical interaction with the drug substrates of CYP2D6. Rhein, exhibits only low potential to cause in vivo inhibition.

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Does Crizotinib Auto-Inhibit CYP3A in vivo?

Pharmacology ◽

10.1159/000506996 ◽

2020 ◽

Vol 105 (11-12) ◽

pp. 715-718

Author(s):

Abigail R. Bland ◽

Nensi Shrestha ◽

Rhonda J. Rosengren ◽

John C. Ashton

Keyword(s):

Lung Cancer ◽

Cytochrome P450 ◽

Western Blot ◽

Anaplastic Lymphoma Kinase ◽

Kinase Inhibitor ◽

Cyp3a Activity ◽

Cytochrome P450 3A ◽

Anaplastic Lymphoma

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin N-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.

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In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol

Interdisciplinary Toxicology ◽

10.2478/v10102-011-0014-x ◽

2011 ◽

Vol 4 (2) ◽

pp. 78-84 ◽

Cited By ~ 5

Author(s):

Galia Zamaratskaia ◽

Martin Rasmussen ◽

Isabelle Herbin ◽

Bo Ekstrand ◽

Vladimir Zlabek

Keyword(s):

Cytochrome P450 ◽

Inhibitory Effect ◽

17Β Estradiol ◽

Cyp2e1 Activity ◽

High Concentrations ◽

Testicular Steroids ◽

Sexually Mature

In vitro inhibition of porcine cytochrome P450 by 17β-estradiol and 17α-estradiol Sexually mature pigs are known to possess high concentrations of testicular steroids, which have been shown to change the activities of cytochrome P450 in vitro. The aim of the present study was to evaluate the regulation of CYP1A and CYP2E1 activity by the steroids dihydrotestosterone (DHT), 3β-androstenol, 17β-estradiol and 17α-estradiol. Catalytic activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) were used as markers of CYP1A activities, while p-nitrophenol hydroxylase (PNPH) was used as a marker of CYP2E1 activities. Of the steroids tested, only 17β-estradiol and 17α-estradiol inhibited EROD and MROD activities. This inhibition was observed when a steroid concentration of 100 μM was used, while lower concentrations showed no inhibitory effect. PNPH activities were inhibited only by 100 μM of 17β-estradiol. The significance of these results in vivo is unknown because inhibition was only found when concentrations of estrogens higher than physiological levels were used. Nevertheless, the results provided further evidence on the important role of estrogens in regulation of porcine cytochrome P450 activities.

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