Chirality Matters: Biological Activity of Optically Pure Silybin and Its Congeners

This review focuses on the specific biological effects of optically pure silymarin flavo-nolignans, mainly silybins A and B, isosilybins A and B, silychristins A and B, and their 2,3-dehydro derivatives. The chirality of these flavonolignans is also discussed in terms of their analysis, preparative separation and chemical reactions. We demonstrated the specific activities of the respective diastereomers of flavonolignans and also the enantiomers of their 2,3-dehydro derivatives in the 3D anisotropic systems typically represented by biological systems. In vivo, silymarin flavonolignans do not act as redox antioxidants, but they play a role as specific ligands of biological targets, according to the “lock-and-key” concept. Estrogenic, antidiabetic, anticancer, antiviral, and antiparasitic effects have been demonstrated in optically pure flavonolignans. Potential application of pure flavonolignans has also been shown in cardiovascular and neurological diseases. Inhibition of drug-metabolizing enzymes and modulation of multidrug resistance activity by these compounds are discussed in detail. The future of “silymarin applications” lies in the use of optically pure components that can be applied directly or used as valuable lead structures, and in the exploration of their true molecular effects.

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Daikenchuto (TU-100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal

Pharmacology Research & Perspectives ◽

10.1002/prp2.361 ◽

2017 ◽

Vol 5 (5) ◽

pp. e00361 ◽

Cited By ~ 3

Author(s):

Kentaro Nobutani ◽

Jun Miyoshi ◽

Mark W. Musch ◽

Mitsue Nishiyama ◽

Junko Watanabe ◽

...

Keyword(s):

Drug Metabolizing Enzymes ◽

Metabolizing Enzymes

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An In Vitro and In Vivo Evaluation of the Effect of Relacorilant on the Activity of Cytochrome P450 Drug Metabolizing Enzymes

The Journal of Clinical Pharmacology ◽

10.1002/jcph.1731 ◽

2020 ◽

Vol 61 (2) ◽

pp. 244-253

Author(s):

Joseph M. Custodio ◽

Kirsteen M. Donaldson ◽

Hazel J. Hunt

Keyword(s):

Cytochrome P450 ◽

Drug Metabolizing Enzymes ◽

In Vivo Evaluation ◽

Metabolizing Enzymes

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Pulmonary Metabolism of Substrates for Key Drug-Metabolizing Enzymes by Human Alveolar Type II Cells, Human and Rat Lung Microsomes, and the Isolated Perfused Rat Lung Model

Pharmaceutics ◽

10.3390/pharmaceutics12020117 ◽

2020 ◽

Vol 12 (2) ◽

pp. 117

Author(s):

Katarina Rubin ◽

Pär Ewing ◽

Erica Bäckström ◽

Anna Abrahamsson ◽

Britta Bonn ◽

...

Keyword(s):

Human Lung ◽

Limit Of Detection ◽

Lung Model ◽

Alveolar Type ◽

Metabolic Clearance ◽

Drug Metabolizing Enzymes ◽

Type Ii ◽

Rat Lung ◽

Metabolizing Enzymes

Significant pulmonary metabolism of inhaled drugs could have drug safety implications or influence pharmacological effectiveness. To study this in vitro, lung microsomes or S9 are often employed. Here, we have determined if rat and human lung microsomes are fit for purpose or whether it is better to use specific cells where drug-metabolizing enzymes are concentrated, such as alveolar type II (ATII) cells. Activities for major hepatic and pulmonary human drug-metabolizing enzymes are assessed and the data contextualized towards an in vivo setting using an ex vivo isolated perfused rat lung model. Very low rates of metabolism are observed in incubations with human ATII cells when compared to isolated hepatocytes and fewer of the substrates are found to be metabolized when compared to human lung microsomal incubations. Reactions selective for flavin-containing monooxygenases (FMOs), CYP1B1, CYP2C9, CYP2J2, and CYP3A4 all show significant rates in human lung microsomal incubations, but all activities are higher when rat lung microsomes are used. The work also demonstrates that a lung microsomal intrinsic clearance value towards the lower limit of detection for this parameter (3 µL/min/mg protein) results in a very low level of pulmonary metabolic clearance during the absorption period, for a drug dosed into the lung in vivo.

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