Effects of Radix Astragali and Radix Rehmanniae, the components of an anti-diabetic foot ulcer herbal formula, on metabolism of model CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 probe substrates in pooled human liver microsomes and specific CYP isoforms

Bakuchicin is a furanocoumarin isolated fromPsoralea corylifoliaand shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinantcDNA-expressedCYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetinO-deethylation with an IC50value of 0.43 μM in HLMs. It was confirmed by human recombinantcDNA-expressedCYP1A1 and CYP1A2 with aKivalue of 0.11 μM and 0.32 μM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.

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Inhibition of Cytochrome P450 Activities by Sophora flavescens Extract and Its Prenylated Flavonoids in Human Liver Microsomes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2673769 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Daeun Yim ◽

Min Jung Kim ◽

Yumi Shin ◽

Su-Jun Lee ◽

Jae Gook Shin ◽

...

Keyword(s):

Cytochrome P450 ◽

Human Liver ◽

East Asian ◽

Liver Microsomes ◽

Human Liver Microsomes ◽

Pharmacological Properties ◽

Asian Countries ◽

Sophora Flavescens ◽

Prenylated Flavonoids ◽

Cyp Isoforms

Sophora flavescens possesses several pharmacological properties and has been widely used for the treatment of diarrhea, inflammation, abscess, dysentery, and fever in East Asian countries. S. flavescens is a major source of prenylated flavonoids, such as sophoraflavone and kushenol. In this study, we examined the effects of S. flavescens extract and its prenylated flavonoids on cytochrome P450 (CYP) isoform activity in human liver microsomes. The extract inhibited CYP2C8, CYP2C9, CYP2C19, and CYP3A activities, with IC50 values of 1.42, 13.6, 19.1, and 50 µg/mL, respectively. CYP2B6 was only inhibited in human liver microsomes preincubated with the extract. CYP3A4 was more strongly inhibited by the extract in the presence of NADPH, suggesting that the extract may inhibit CYP2B6 and CYP3A4 via mechanism-based inactivation. Prenylated flavonoids also inhibited CYP isoforms with different selectivity and modes of action. Kushenol I, leachianone A, and sophoraflavone G inhibited CYP2B6, whereas kushenol C, kushenol I, kushenol M, leachianone A, and sophoraflavone G inhibited CYP3A4 via mechanism-based inhibition. Our results suggest that S. flavescens may contribute to herb–drug interactions when coadministered with drugs metabolized by CYP2B6, CYP2C8, CYP2C9, and CYP3A4.

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Interaction of serum proteins with CYP isoforms in human liver microsomes: inhibitory effects of human and bovine albumin, alpha-globulins, alpha-1-acid glycoproteins and gamma-globulins on CYP2C19 and CYP2D6

Life Sciences ◽

10.1016/s0024-3205(03)00093-6 ◽

2003 ◽

Vol 72 (17) ◽

pp. 1953-1962 ◽

Cited By ~ 9

Author(s):

Bang Qian Xu ◽

Mikio Ishii ◽

Li Rong Ding ◽

Nancy E Fischer ◽

Tadanobu Inaba

Keyword(s):

Human Liver ◽

Serum Proteins ◽

Liver Microsomes ◽

Human Liver Microsomes ◽

Inhibitory Effects ◽

Bovine Albumin ◽

Cyp Isoforms

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Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.11.3464-3469.2003 ◽

2003 ◽

Vol 47 (11) ◽

pp. 3464-3469 ◽

Cited By ~ 21

Author(s):

Ji-Young Park ◽

Kyoung-Ah Kim ◽

Su-Lyun Kim

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Human Liver ◽

Liver Microsomes ◽

Inhibitory Effect ◽

Human Liver Microsomes ◽

Human Cytochrome ◽

Cytochrome P450 Isoforms ◽

Potent Inhibitory Effect ◽

Cyp Isoforms

ABSTRACT The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4′-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations (inhibitory constant [Ki ] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) μM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (Ki ) of 375.9 (75.8) μM. The mechanism of the drug interaction reported between chloramphenicol and phenytoin, which results in the elevation of plasma phenytoin concentrations, is clinically assumed to result from the inhibition of CYP2C9 by chloramphenicol. However, using human liver microsomes and cDNA-expressed CYPs, we showed this interaction arises from the inhibition of CYP2C19- not CYP2C9-catalyzed phenytoin metabolism. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.

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Metabolism of Diterpenoids Derived from the Bark of Cinnamomum cassia in Human Liver Microsomes

Pharmaceutics ◽

10.3390/pharmaceutics13081316 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1316

Author(s):

Su Min Choi ◽

Van Cong Pham ◽

Sangkyu Lee ◽

Jeong Ah Kim

Keyword(s):

High Resolution ◽

Human Liver ◽

Liver Microsomes ◽

Antibacterial Activities ◽

Human Liver Microsomes ◽

Pharmacological Effects ◽

Cinnamomum Cassia ◽

Orbitrap Mass Spectrometer ◽

Cyp Isoforms ◽

Flavoring Agent

Cinnamomum cassia L. is used as a spice and flavoring agent as well as a traditional medicine worldwide. Diterpenoids, a class of compounds present in C. cassia, have various pharmacological effects, such as anti-inflammatory, antitumor, and antibacterial activities; however, there are insufficient studies on the metabolism of diterpenoids. In this study, the metabolism of seven diterpenoids, namely, anhydrocinnzeylanol, anhydrocinnzeylanine (AHC), cinncassiol A, cinncassiol B, cinnzeylanol, cinnzeylanone, and cinnzeylanine, obtained from the bark of C. cassia was studied in human liver microsomes (HLMs). All studied diterpenoids, except for AHC, exhibited strong metabolic stability; however, AHC was rapidly metabolized to 3% in HLMs in the presence of β-NADPH. Using a high-resolution quadrupole-orbitrap mass spectrometer, 20 metabolites were identified as dehydrogenated metabolites (M1–M3), dehydrogenated and oxidated metabolites (M4–M10), mono-oxidated metabolites (M11–M13), or dioxidated metabolites (M14–M20). In addition, CYP isoforms involved in AHC metabolism were determined by profiling metabolites produced after incubation in 11 recombinant cDNA-expressed CYP isoforms. Thus, the diterpenoid compound AHC was identified in a metabolic pathway involving CYP3A4 in HLMs.

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