Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation

Tyrosine kinase inhibitors are a rapidly expanding class of molecular targeted therapies for the treatment of various types of cancer and other diseases. An increasing number of clinically important small molecule tyrosine kinase inhibitors have been shown to undergo cytochrome P450-mediated bioactivation to form chemically reactive, potentially toxic products. Metabolic activation of tyrosine kinase inhibitors is proposed to contribute to the development of serious adverse reactions, including idiosyncratic hepatotoxicity. This article will review recent findings and ongoing studies to elucidate the link between drug metabolism and tyrosine kinase inhibitor-associated hepatotoxicity.

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Metabolic Activation of Procarcinogens by Human Cytochrome P450 Enzymes in Microsomes of Adult and Fetal Livers and of Adult Lungs

Drug Metabolism and Pharmacokinetics ◽

10.2133/dmpk.10.supplement_126 ◽

1995 ◽

Vol 10 (supplement) ◽

pp. 126-129

Author(s):

Tsutomu Shimada ◽

Hiroshi Yamazaki ◽

F. Peter Guengerich

Keyword(s):

Cytochrome P450 ◽

Metabolic Activation ◽

Cytochrome P450 Enzymes ◽

Human Cytochrome

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The Antiaggregating Activity of Clopidogrel Is due to a Metabolic Activation by the Hepatic Cytochrome P450-1A

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648859 ◽

1994 ◽

Vol 72 (02) ◽

pp. 313-317 ◽

Cited By ~ 200

Author(s):

P Savi ◽

J Combalbert ◽

C Gaich ◽

M-C Rouchon ◽

J-P Maffrand ◽

...

Keyword(s):

Cytochrome P450 ◽

Metabolic Activation ◽

Cytochrome P450 Enzymes ◽

Specific Antibodies ◽

Specific Induction ◽

Antithrombotic Effects ◽

Cytochrome P450 1A ◽

Hepatic Cytochrome

SummaryClopidogrel and ticlopidine are two well known selective anti-ADP agents which are inactive in vitro and must be administered in vivo to fully exhibit their antiaggregating and antithrombotic effects. Since previous studies have clearly demonstrated that the activation steps take place in the liver, we examined the effect of specific induction or inhibition of cytochrome P450 subfamilies on the antiaggregating activity of clopidogrel. SKF 525-A, a global cytochrome P450 inhibitor, dramatically decreased the antiaggregating effect of clopidogrel, therefore indicating that cytochrome P450 enzymes are involved in the hepatic activation of clopidogrel. The efficacy of clopidogrel was increased in animals pretreated with 3-methylcholanthrene and (3-naphthoflavone, indicating that the cytochrome P450-1A subfamily pathway was mainly involved in the activating metabolism of clopidogrel. The use of specific antibodies directed against the various cytochrome P450 subfamilies ascertained this observation.

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Biomimetic Oxidation of Benzofurans with Hydrogen Peroxide Catalyzed by Mn(III) Porphyrins

Catalysts ◽

10.3390/catal10010062 ◽

2020 ◽

Vol 10 (1) ◽

pp. 62

Author(s):

Susana L. H. Rebelo ◽

Sónia M. G. Pires ◽

Mário M. Q. Simões ◽

Baltazar de Castro ◽

M. Graça P. M. S. Neves ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cytochrome P450 ◽

Catalytic Oxidation ◽

Room Temperature ◽

Metabolic Activation ◽

Reaction Pathways ◽

Cytochrome P450 Enzymes ◽

Methyl Group ◽

Biomimetic Oxidation ◽

Work Up

The modelling of metabolic activation of the benzofuran nucleus is important to obtain eco-sustainable degradation methods and to understand the related mechanisms. The present work reports the catalytic oxidation of benzofuran, 2-methylbenzofuran, and 3-methylbenzofuran by hydrogen peroxide, at room temperature, in the presence of different Mn(III) porphyrins as models of cytochrome P450 enzymes. Conversions above 95% were attained for all the substrates. The key step is the formation of epoxides, which undergo different reaction pathways depending on factors, such as the position of the methyl group and the reaction and work-up conditions used.

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