Determination of oroxylin A and oroxylin A 7-O-d-glucuronide in HepG2 cell lysate and subcellular fractions with SPE-UPLC–MS/MS: Cellular pharmacokinetic study to indicate anti-cancer mechanisms

Zhang, Qing; Cong, Danhua; An, Dongchen; Fan, Ali; Liu, Qi; Yi, Yingyue; Song, Zijing; Chen, Xijing; Lu, Yang; Zhao, Di; He, Ling

doi:10.1016/j.jpba.2018.03.019

Cited by 20 publications

(12 citation statements)

References 22 publications

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“…Nevertheless, it has been suggested that baicalein is metabolized to oroxylin A by catechol‐O‐methyltransferase, which implies that baicalein may be relatively short lived compared with oroxylin A since catechol‐O‐methyltransferase is abundant in the human body (Zhang et al, ). A recent study from our group (Zhang et al, ) showed that oroxylin A has a specific distribution in cellular nuclei of HepG2 cells. Although the cellular concentrations of oroxylin A was not obtained, it is suggested that the specific type of cellular distribution might imply the anticancer effect of oroxylin A and related flavonoids.…”

Section: Discussionmentioning

confidence: 87%

“…In addition, chlorzoxazone was used as the internal standard in the present study due to the similarity of retention performance with the analytes and the stability of high response to tandem MS/MS. Moreover, this internal standard has been used in a similar previously published assay as well (Zhang et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…After incubating for 15 min, 1‐μM 17β‐estradiol was added and then incubated for 24 hr. The concentrations of 17β‐estradiol and each flavonoid were used according to the previous researches in cancer cells (Chan, Chen, Tsang, & Leung, ; Takemura, Uchiyama, et al, ; Huang, Chiang, & Chen, ; Cheng et al, ; Wang et al, ; Zhang et al, ). Dimethyl sulfoxide (0.1% v/v ) was used as a negative control.…”

Section: Methodsmentioning

confidence: 99%

“…Baicalein and oroxylin A (a methylated metabolite of baicalein in human body; Figure b; Zhang et al, ), active flavonoids extracted from the plant Scutellaria baicalensis Georgi radix, contain multiple hydroxyl and/or methoxyl substituents on their B‐rings (Figure b; Lu, Guo, & Zhao, ; Wang et al, ). Moreover, substantial biotransformation between baicalein or oroxylin A and their corresponding glycosides (baicalin and oroxylin A 7‐O‐β‐D‐glucuronide, respectively) was found in human body (Figure b; Pang et al, ; Zhang et al, ). These glycosides also contain the key structural features of inhibiting CYP1B1 (Figure b); however, their inhibitory effects have not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

Song

et al. 2019

Phytotherapy Research

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4-OHE2) from 17β-estradiol plays an important role in the progression of human breast cancer, while the biotransformation of 17β-estradiol to 2-hydroxyestradiol mediated by cytochrome P450 1A1 (CYP1A1) is considered as a less harmful pathway. In this study, inhibitory effects of flavonoids baicalein and oroxylin A, a metabolite of baicalein in human body, on CYP1A1 and 1B1 activities were investigated in vitro. The inhibition intensities of baicalein and oroxylin A towards CYP1B1 were greater than towards CYP1A1 with a mixed mechanism. In addition, oroxylin A showed a stronger inhibitory effect than baicalein towards the CYP1B1-mediated 17β-estradiol 4-hydroxylation, with the IC 50 values of 0.0146 and 2.27 μM, respectively. Docking studies elucidated that oroxylin A had a stronger binding affinity than baicalein for CYP1B1. In MCF-7 cells, compared with baicalein-treated groups, oroxylin A with lower doses decreased and increased the formation of 4-OHE2 and 2-hydroxyestradiol, respectively, with a preferential induction of mRNA of CYP1A1 over CYP1B1. In conclusion, this study demonstrated that oroxylin A showed a stronger inhibitory effect than baicalein on CYP1B1-mediated 4-OHE2 formation in MCF-7 cells, providing crucial implications for their possibly preventive/therapeutic potential against breast cancer via inhibition of CYP1B1, particularly of oroxylin A.

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Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

Song

et al. 2019

Phytotherapy Research

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“…In vitro data on HepG2 culture cells have shown that inside the cells, oroxylin A is distributed predominantly in the nucleus, whereas its glucuronide metabolite (oroxylin A 7- O - d -glucuronide) accumulates predominantly in mitochondria [135].…”

Section: Distributionmentioning

confidence: 99%

Pharmacokinetics of B-Ring Unsubstituted Flavones

et al. 2019

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B-ring unsubstituted flavones (of which the most widely known are chrysin, baicalein, wogonin, and oroxylin A) are 2-phenylchromen-4-one molecules of which the B-ring is devoid of any hydroxy, methoxy, or other substituent. They may be found naturally in a number of herbal products used for therapeutic purposes, and several have been designed by researchers and obtained in the laboratory. They have generated interest in the scientific community for their potential use in a variety of pathologies, and understanding their pharmacokinetics is important for a grasp of their optimal use. Based on a comprehensive survey of the relevant literature, this paper examines their absorption (with deglycosylation as a preliminary step) and their fate in the body, from metabolism to excretion. Differences among species (inter-individual) and within the same species (intra-individual) variability have been examined based on the available data, and finally, knowledge gaps and directions of future research are discussed.

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Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2

Zhong,

Gong,

Meng

et al. 2024

Advanced Science

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The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG‐M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG‐M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC‐MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH‐mediated OXPHOS pathway, thereby inducing MG‐M2 polarization, promoting neuronal survival and exerting an anti‐AD role is elucidated.

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Determination of oroxylin A and oroxylin A 7-O-d-glucuronide in HepG2 cell lysate and subcellular fractions with SPE-UPLC–MS/MS: Cellular pharmacokinetic study to indicate anti-cancer mechanisms

Cited by 20 publications

References 22 publications

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

Oroxylin A, a methylated metabolite of baicalein, exhibits a stronger inhibitory effect than baicalein on the CYP1B1‐mediated carcinogenic estradiol metabolite formation

Pharmacokinetics of B-Ring Unsubstituted Flavones

Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2

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