Current High-Throughput Approaches of Screening Modulatory Effects of Xenobiotics on Cytochrome P450 (CYP) Enzymes

Ung, Yee Tze; Ong, Chin Eng; Pan, Yan

doi:10.3390/ht7040029

Cited by 24 publications

(17 citation statements)

References 47 publications

(51 reference statements)

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“…S. cerevisiae was the first system and one of the top choices for heterologously expressing eukaryotic P450s, and various P450s have been functionally expressed in S. cerevisiae (van Leeuwen et al, 2012; Oeda et al, 1985; Ung et al, 2018). Urban et al (1994) successfully expressed Helianthus tuberosus P450 (CYP73, cinnamate 4‐hydroxylase) in S. cerevisiae for the production of p‐coumarate.…”

Section: Yeast Expression Systems For Eukaryotic P450smentioning

confidence: 99%

Functional expression of eukaryotic cytochrome P450s in yeast

Jiang

Huang

Cai

et al. 2020

Biotech & Bioengineering

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Cytochrome P450 enzymes (P450s) are a superfamily of heme‐thiolate proteins widely existing in various organisms. Due to their key roles in secondary metabolism, degradation of xenobiotics, and carcinogenesis, there is a great demand to heterologously express and obtain a sufficient amount of active eukaryotic P450s. However, most eukaryotic P450s are endoplasmic reticulum‐localized membrane proteins, which is the biggest challenge for functional expression to high levels. Furthermore, the functions of P450s require the cooperation of cytochrome P450 reductases for electron transfer. Great efforts have been devoted to the heterologous expression of eukaryotic P450s, and yeasts, particularly Saccharomyces cerevisiae are frequently considered as the first expression systems to be tested for this challenging purpose. This review discusses the strategies for improving the expression and activity of eukaryotic P450s in yeasts, followed by examples of P450s involved in biosynthetic pathway engineering.

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Section: Yeast Expression Systems For Eukaryotic P450smentioning

confidence: 99%

Functional expression of eukaryotic cytochrome P450s in yeast

Jiang

Huang

Cai

et al. 2020

Biotech & Bioengineering

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“…However, herb-drug interactions (HDI) might occur during the process of clinical application. The important metabolic enzyme, cytochrome P450, plays a vital role in drug metabolism [35]. CYP450 is a superfamily of enzymes, and the majority of CYPs involved in drug metabolism include CYP3A4/5, CYP2D6, CYP1A2, CYP2B6, CYP2C19, CYP2A6, and CYP2J2.…”

Section: Discussionmentioning

confidence: 99%

“…CYP450 is a superfamily of enzymes, and the majority of CYPs involved in drug metabolism include CYP3A4/5, CYP2D6, CYP1A2, CYP2B6, CYP2C19, CYP2A6, and CYP2J2. When one of the drugs inhibits CYP enzyme activity, drug-drug interactions may occur, affecting the metabolism of the coadministered drug [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Effect of Naoxintong Capsules on the Activities of CYP450 and Metabolism of Metoprolol Tartrate in Rats Evaluated by Probe Cocktail and Pharmacokinetic Methods

Ouyang

Shen

Huang

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Naoxintong capsule (NXT), a prescribed Chinese medicine, has been used clinically for more than 20 years and is widely received by patients. We determined five probe drugs, namely, omeprazole (CYP2C19), midazolam (CYP3A4), phenacetin (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) to study the potential influences of NXT on the activities of CYP enzymes and assessed the pharmacokinetics effect of NXT on metoprolol tartrate in rat plasma. The study showed that AUC(0–24) and AUC(0–∞) of midazolam (CYP3A4) in NXT coadministration group (283.7 ± 65.2 h·ng·mL−1 and 292.0 ± 75.1 h·ng·mL−1 in group B; 295.7 ± 62.7 h·ng·mL−1 and 299.5 ± 60.0 h·ng·mL−1 in group C) were significantly decreased as compared to another group (416.8 ± 82.3 h·ng·mL−1 and 424.9 ± 77.9 h·ng·mL−1 in group A), while that of dextromethorphan (CYP2D6) showed an opposite tendency (540.7 ± 119.7 h·ng·mL−1 and 595.3 ± 122.2 h·ng·mL−1 in group A, 760.6 ± 184.9 h·ng·mL−1 and 788.7 ± 211.0 h·ng·mL−1 in group B, and 734.3 ± 118.5 h·ng·mL−1 and 757.2 ± 105.4 h·ng·mL−1 in group C). Moreover, NXT preadministration can enhance the metabolism of metoprolol tartrate and reduce the metabolism of O-demethylmetoprolol. The results indicated that NXT had potential effects in inducing CYP3A4 and inhibiting CYP2D6 in the metabolism of metoprolol tartrate. It suggests that patients who coadministered NXT and metoprolol tartrate should be advised of potential herb-drug interactions (HDIs) to reduce therapeutic failure or accelerated toxicity of conventional drug treatment.

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“…The fluorescence-based approach for screening has several advantages: it is faster and much less expensive than LC-MS methods. Data can be generated quickly without compromising data quality [ 10 , 36 , 71 , 72 ].…”

Section: Applicationsmentioning

confidence: 99%

Coumarin-Based Profluorescent and Fluorescent Substrates for Determining Xenobiotic-Metabolizing Enzyme Activities In Vitro

Raunio

Pentikäinen

Juvonen

2020

IJMS

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in vivo methods, such as spectrophotometric, fluorometric, mass spectrometric,and radioactivity-based techniques. In fluorescence-based assays, the reaction produces a fluorescentproduct from a nonfluorescent substrate or vice versa. Fluorescence-based enzyme assays areusually highly sensitive and specific, allowing measurements on small specimens of tissues withlow enzyme activities. Fluorescence assays are also amenable to miniaturization of the reactionmixtures and can thus be done in high throughput. 7-Hydroxycoumarin and its derivatives arewidely used as fluorophores due to their desirable photophysical properties. They possess a large -conjugated system with electron-rich and charge transfer properties. This conjugated structure leadsto applications of 7-hydroxycoumarins as fluorescent sensors for biological activities. We describe inthis review historical highlights and current use of coumarins and their derivatives in evaluatingactivities of the major types of xenobiotic-metabolizing enzyme systems. Traditionally, coumarinsubstrates have been used to measure oxidative activities of cytochrome P450 (CYP) enzymes. For thispurpose, profluorescent coumarins are very sensitive, but generally lack selectivity for individual CYPforms. With the aid of molecular modeling, we have recently described several new coumarin-basedsubstrates for measuring activities of CYP and conjugating enzymes with improved selectivity.

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Current High-Throughput Approaches of Screening Modulatory Effects of Xenobiotics on Cytochrome P450 (CYP) Enzymes

Cited by 24 publications

References 47 publications

Functional expression of eukaryotic cytochrome P450s in yeast

Functional expression of eukaryotic cytochrome P450s in yeast

Effect of Naoxintong Capsules on the Activities of CYP450 and Metabolism of Metoprolol Tartrate in Rats Evaluated by Probe Cocktail and Pharmacokinetic Methods

Coumarin-Based Profluorescent and Fluorescent Substrates for Determining Xenobiotic-Metabolizing Enzyme Activities In Vitro

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