Cytochrome P450

Shankar, Kartik; Mehendale, Harihara M.

doi:10.1016/b978-0-12-386454-3.00299-2

“…Compared with normal hepatocytes, HepG2 cells exhibit a decreased expression level of CYP genes [ 102 , 127 , 128 ], which play a decisive role in the metabolism of endogenous and exogenous molecules [ 128 , 129 , 130 ]. Moreover, reduced expression levels of these genes are also observed in tumor cells in HCC and HB, which, as expected, correlate with a low survival estimates [ 131 ].…”

Section: Comparison Of Hepg2 Normal Hepatocyte Hb and Hccmentioning

confidence: 99%

The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

Arzumanian

¹

,

Kiseleva

²

,

Poverennaya

³

2021

IJMS

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Liver cancer is the third leading cause of cancer death worldwide. Representing such a dramatic impact on our lives, liver cancer is a significant public health concern. Sustainable and reliable methods for preventing and treating liver cancer require fundamental research on its molecular mechanisms. Cell lines are treated as in vitro equivalents of tumor tissues, making them a must-have for basic research on the nature of cancer. According to recent discoveries, certified cell lines retain most genetic properties of the original tumor and mimic its microenvironment. On the other hand, modern technologies allowing the deepest level of detail in omics landscapes have shown significant differences even between samples of the same cell line due to cross- and mycoplasma infection. This and other observations suggest that, in some cases, cell cultures are not suitable as cancer models, with limited predictive value for the effectiveness of new treatments. HepG2 is a popular hepatic cell line. It is used in a wide range of studies, from the oncogenesis to the cytotoxicity of substances on the liver. In this regard, we set out to collect up-to-date information on the HepG2 cell line to assess whether the level of heterogeneity of the cell line allows in vitro biomedical studies as a model with guaranteed production and quality.

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“…The high volume of distribution and low binding of plasma protein by the drug further ascertain the good bioavailability and hinted at the potential good therapeutic index of the compounds but were non-BBB permeant (except for catechin) (Figure 8(b), Table 5). Cytochrome P450 (CYP450) is a 14 Oxidative Medicine and Cellular Longevity heme containing enzyme family that play central metabolic role on exogenous and endogenous substances [99]. Hence, impeding the activities of these enzyme isoforms may lead to deficient drug metabolism and toxic drug accumulation.…”

Section: Drug-admet and Likeness Modeling Of Compoundsmentioning

confidence: 99%

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

Alozieuwa

¹

,

Lawal

²

,

Sani³

et al. 2022

Oxidative Medicine and Cellular Longevity

12

2

0

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The present study evaluated the polyphenolic contents and hypoglycemic, antioxidant, and anti-inflammatory effects of the diethyl ether fraction of Thespesia garckeana using various in vitro and in vivo models. Total phenol and flavonoid contents of the extract were 613.65 ± 2.38 and 152.83 ± 1.56 mg/100 g dry weight, respectively. The extract exhibited in vitro antioxidant activities against DPPH, FRAP, LPO, and ABTS with respective half-maximal inhibitory concentration (IC50) values of 30.91 ± 0.23 , 16.81 ± 0.51 , 41.29 ± 1.82 , and 42.39 ± 2.24 μg/mL. In vitro anti-inflammatory studies using membrane stabilization, protein denaturation, and proteinase activities revealed the effectiveness of the extract with respective IC50 values of 54.45 ± 2.89 , 93.62 ± 3.04 , and 56.60 ± 2.34 μg/mL, while in vitro hypoglycemic analysis of the extract revealed inhibition of α-amylase (IC50 64.59 ± 3.29 μg/mL) and enhancement of glucose uptake by yeast cells. Interestingly, the extract demonstrated in vivo hypoglycemic and anti-inflammatory effects in streptozotocin- (STZ-) induced diabetic and xylene-induced ear swelling models, respectively. In addition, the extract improved insulin secretion, attenuated pancreatic tissue distortion and oxidative stress, and increased the activities of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH), while reducing the concentration of LPO in the diabetic rats. A high-performance liquid chromatography (HPLC) analysis identified the presence of catechin ( 6.81 e − 1 ppm), rutin ( 8.46 e − 1 ppm), myricetin, apigenin ( 4.019 e − 1 ppm), and luteolin (15.09 ppm) with respective retention times (RTs) of 13.64, 24.269, 27.781, 29.58, and 32.23 min, and these were subjected to a pharmacoinformatics analysis, which revealed their drug-likeness and good pharmacokinetic properties. A docking analysis hinted at the potential of luteolin, the most abundant compound in the extract, for targeting glucose-metabolizing enzymes. Thus, the present study provides preclinical insights into the bioactive constituents of T. garckeana, its antioxidant and anti-inflammatory effects, and its potential for the treatment of diabetes.

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“…In mammals, CYP family 1, 2, 3 and 4 are involved in detoxification, steroid and eicosanoids metabolism. 20 In humans, CYP family 1, 2, 3 and 4 and to a lesser extent CYP family 5, 8, 19, 21 and 26 are involved in xenobiotic metabolism. 20 The CYP enzymes are predisposed to inhibition or induction by xenobiotics including herbal medications that comprise mixtures of phytochemicals.…”

Section: Introductionmentioning

confidence: 99%

“…20 In humans, CYP family 1, 2, 3 and 4 and to a lesser extent CYP family 5, 8, 19, 21 and 26 are involved in xenobiotic metabolism. 20 The CYP enzymes are predisposed to inhibition or induction by xenobiotics including herbal medications that comprise mixtures of phytochemicals. 21 Phytochemicals such as resveratrol and quercetin have been reported to significantly inhibit CYP3A4 which translates to reduced clearance and subsequent toxicity from other CYP3A4 substrates in humans.…”

Section: Introductionmentioning

confidence: 99%

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

Lim

¹

,

Loo

²

,

Alshagga

³

et al. 2022

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Cathine is the stable form of cathinone, the major active compound found in khat ( Catha edulis Forsk) plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities in vitro and in vivo. With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput in vitro fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs’ active sites. The half maximal inhibitory concentration (IC50) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in Ki analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with Ki value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and in vitro outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.

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Cytochrome P450

Cited by 27 publications

References 7 publications

The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

The Curious Case of the HepG2 Cell Line: 40 Years of Expertise

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

Protein-Ligand Identification andIn VitroInhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s

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