Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Fang, Ping; Zheng, Xiang; He, Jiayang; Ge, Honglei; Tang, Pengfei; Cai, Jian‐Ping; Hu, Guoxin

doi:10.2147/dddt.s133814

Cited by 12 publications

(8 citation statements)

References 30 publications

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“…Previously, we and others have shown that pCBs are metabolized by various human CYPs to form novel oxidized products. 23,[48][49][50] Additionally, many of the pCBs tested, including CBD have been shown to inhibit CYPs. 41 Herein, we explore the differences in pCB binding, metabolism, and inhibition of CYP2D6 and its mutants.…”

Section: Introductionmentioning

confidence: 99%

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

et al. 2021

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Cytochrome P450 2D6 (CYP2D6) is primarily expressed in the liver and in the central nervous system. It is known to be highly polymorphic in nature. It metabolizes several endogenous substrates such as anandamide (AEA). Concomitantly, it is involved in phase 1 metabolism of several antidepressants, antipsychotics, and other drugs. Research in the field of phytocannabinoids (pCBs) has recently accelerated owing to its legalization and increasing medicinal use for pain and inflammation. The primary component of cannabis is THC, which is well known for its psychotropic effects. Since CYP2D6 is an important brain and liver P450 and is known to be inhibited by CBD, we investigated the interactions of four important highly prevalent CYP2D6 polymorphisms with selected phytocannabinoids (CBD, THC, CBDV.THCV, CBN, CBG, CBC, β-carophyllene) that are rapidly gaining popularity. We show that there is differential binding of CYP2D6*17 to pCBs as compared to WT CYP2D6. We also perform a more detailed comparison of WT and *17 CYP2D6 which reveals the possible regulation of AEA *

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Section: Introductionmentioning

confidence: 99%

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

et al. 2021

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“…Additionally, the concentrations of CBN could not be detected for CYP3A4.6, .20, and .30. Similar with ibrutinib, gefitinib, and regorafenib, − CBZ was prone to substrate inhibition with K si of all tested CYP3A4 variants averaging from 3.61 to 135.07 μM.…”

Section: Resultsmentioning

confidence: 89%

Characterization of Genetic Variation in CYP3A4 on the Metabolism of Cabozantinib in Vitro

Lin

et al. 2019

Chem. Res. Toxicol.

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Cabozantinib is a multityrosine kinase inhibitor and has a wide range of applications in the clinic, whose metabolism is predominately dependent on CYP3A4. This study was performed to characterize the enzymatic properties of 29 CYP3A4 alleles toward cabozantinib and the functional changes of five selected alleles (the wild-type, CYP3A4.2.8.14 and .15) toward cabozantinib in the presence of ketoconazole. Cabozantinib, 1−100 μM, with/without the presence of ketoconazole and CYP3A4 enzymes in the incubation system went through 30 min incubation at 37 °C, and the concentrations of cabozantinib N-oxide were quantified by UPLC−MS/MS to calculate the corresponding kinetic parameters of each variant. Collectively, without the presence of ketoconazole, most variants displayed defective enzymatic activities in different degrees, and only CYP3A4.14 and .15 showed significantly augmented enzymatic activities. With the presence of ketoconazole, five tested CYP3A4 alleles, even CYP3A4.14 and .15, exhibited obvious reductions in intrinsic clearance. Besides, we compared cabozantinib with regorafenib in relative clearance to confirm that CYP3A4 has the property of substrate specificity. As the first study of CYP3A4 genetic polymorphisms toward cabozantinib, our observations can provide prediction of an individual's capability in response to cabozantinib and guidance for medication and treatment of cabozantinib.

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Section: Resultsmentioning

confidence: 99%

“…28 Because of the significant contribution of CYP2D6 in the metabolism of drugs, discovery of its inhibitors is a key research area in drug discovery programs. 28d Furthermore, the CYP2D6 enzyme has extensively been studied for delineation of the metabolism (O-demethylation and N-demethylation) of approved drugs viz metoprolol, 29 gefitinib, 30 and natural products. 31 To understand the observed trend in differential demethylation reactions (O vs N-demethylation) using CYP2D6-wt and CYP2D6-C (CYP2D6.10 A112V ), molecular modeling studies were conducted.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10^A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme

Williams¹,

Gatchie²,

Bharate

et al. 2018

ACS Omega

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CYP2D6, a cytochrome P450 (CYP) enzyme, metabolizes codeine to morphine. Within the human body, 0–15% of codeine undergoes O-demethylation by CYP2D6 to form morphine, a far stronger analgesic than codeine. Genetic polymorphisms in wild-type CYP2D6 (CYP2D6-wt) are known to cause poor-to-extensive metabolism of codeine and other CYP2D6 substrates. We have established a platform technology that allows stable expression of human CYP genes from chromosomal loci of baker’s yeast cells. Four CYP2D6 alleles, (i) chemically synthesized CYP2D6.1, (ii) chemically synthesized CYP2D6-wt, (iii) chemically synthesized CYP2D6.10, and (iv) a novel CYP2D6.10 variant CYP2D6-C (i.e., CYP2D6.10 A122V ) isolated from a liver cDNA library, were cloned for chromosomal integration in yeast cells. When expressed in yeast, CYP2D6.10 enzyme shows weak activity compared with CYP2D6-wt and CYP2D6.1 which have moderate activity, as reported earlier. Surprisingly, however, the CYP2D6-C enzyme is far more active than CYP2D6.10. More surprisingly, although CYP2D6.10 is a known low metabolizer of codeine, yeast cells expressing CYP2D6-C transform >70% of codeine to morphine, which is more than twice that of cells expressing the extensive metabolizers, CYP2D6.1, and CYP2D6-wt. The latter two enzymes predominantly catalyze formation of codeine’s N-demethylation product, norcodeine, with >55% yield. Molecular modeling studies explain the specificity of CYP2D6-C for O-demethylation, validating observed experimental results. The yeast-based CYP2D6 expression systems, described here, could find generic use in CYP2D6-mediated drug metabolism and also in high-yield chemical reactions that allow the formation of regio-specific dealkylation products.

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Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Cited by 12 publications

References 30 publications

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

Characterization of Genetic Variation in CYP3A4 on the Metabolism of Cabozantinib in Vitro

Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10^A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme

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Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Cited by 12 publications

References 30 publications

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms

Characterization of Genetic Variation in CYP3A4 on the Metabolism of Cabozantinib in Vitro

Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme

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Biotransformation, Using Recombinant CYP450-Expressing Baker’s Yeast Cells, Identifies a Novel CYP2D6.10^A122V Variant Which Is a Superior Metabolizer of Codeine to Morphine Than the Wild-Type Enzyme