scholarly journals Identification of Endogenous Substrates of Orphan Cytochrome P450 Enzymes Through the Use of Untargeted Metabolomics Approaches

2013 ◽  
pp. 71-77 ◽  
Author(s):  
Qian Cheng ◽  
F. Peter Guengerich
Keyword(s):  
Cytochrome P450 ◽  
Untargeted Metabolomics ◽  
Cytochrome P450 Enzymes ◽  
Endogenous Substrates

Cytochrome P450 enzymes: ubiquitous "receptors" for drugs

1991 ◽  
Vol 69 (8) ◽  
pp. 1129-1132 ◽  
Author(s):  
Frank S. LaBella
Keyword(s):  
Cytochrome P450 ◽  
Protein Interactions ◽  
Hormone Receptors ◽  
Radioligand Binding ◽  
Cytochrome P450 Enzymes ◽  
Fatty Acid Derivatives ◽  
Affinity Constants ◽  
Cellular Lipids ◽  
Endogenous Substrates ◽  
The One

Most foreign compounds bind to one or more cytochrome P450 drug-metabolizing isozymes. These heme monooxygenases are most concentrated in the endoplasmic reticulum of liver cells but are present in virtually all biological membranes and in all cells. Some radioligands for known hormone receptors have been found to label, with comparable affinities, specific P450 enzymes. A characteristic feature of P450 enzymes is their broad and overlapping drug specificities, with affinity constants ranging over several orders of magnitude. Because fatty acid derivatives and steroids are endogenous substrates for the P450 enzymes, drugs may interfere with the generation of functional cellular lipids. The functional significance of high-affinity binding of drugs to the oxygenases may, on the one hand, be minimal and reflect extraneous or trivial drug–protein interactions. On the other hand, the drug–P450 union may in other cases mediate the major pharmacological response.Key words: cytochrome P450, radioligand binding, microsomes, sigma receptor, antiestrogen receptor.

scholarly journals Evaluation of Luminogenic Substrates as Probe Substrates for Bacterial Cytochrome P450 Enzymes: Application to Mycobacterium tuberculosis

2019 ◽  
Vol 24 (7) ◽  
pp. 745-754
Author(s):  
Sandra Ortega Ugalde ◽  
Dongping Ma ◽  
James J. Cali ◽  
Jan N. M. Commandeur
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cytochrome P450 ◽  
High Throughput ◽  
High Throughput Screening ◽  
Drug Targets ◽  
High Signal ◽  
Cytochrome P450 Enzymes ◽  
High Enzyme ◽  
Endogenous Substrates ◽  
Selection Of

Several cytochrome P450 enzymes (CYPs) encoded in the genome of Mycobacterium tuberculosis (Mtb) are considered potential new drug targets due to the essential roles they play in bacterial viability and in the establishment of chronic intracellular infection. Identification of inhibitors of Mtb CYPs at present is conducted by ultraviolet-visible (UV-vis) optical titration experiments or by metabolism studies using endogenous substrates, such as cholesterol and lanosterol. The first technique requires high enzyme concentrations and volumes, while analysis of steroid hydroxylation is dependent on low-throughput analytical methods. Luciferin-based luminogenic substrates have proven to be very sensitive substrates for the high-throughput profiling of inhibitors of human CYPs. In the present study, 17 pro-luciferins were evaluated as substrates for Mtb CYP121A1, CYP124A1, CYP125A1, CYP130A1, and CYP142A1. Luciferin-BE was identified as an excellent probe substrate for CYP130A1, resulting in a high luminescence yield after addition of luciferase and adenosine triphosphate (ATP). Its applicability for high-throughput screening was supported by a high Z’-factor and high signal-to-background ratio. Using this substrate, the inhibitory properties of a selection of known inhibitors could be characterized using significantly less protein concentration when compared to UV-vis optical titration experiments. Although several luminogenic substrates were also identified for CYP121A1, CYP124A1, CYP125A1, and CYP142A1, their relatively low yield of luminescence and low signal-to-background ratios make them less suitable for high-throughput screening since high enzyme concentrations will be needed. Further structural optimization of luminogenic substrates will be necessary to obtain more sensitive probe substrates for these Mtb CYPs.

Xenobiotic Metabolising Enzymes: Impact on Pathologic Conditions, Drug Interactions and Drug Design

2019 ◽  
Vol 19 (4) ◽  
pp. 276-291 ◽  
Author(s):  
Eleni A. Rekka ◽  
Panos N. Kourounakis ◽  
Maria Pantelidou
Keyword(s):  
Cytochrome P450 ◽  
The Body ◽  
Phase Iii ◽  
Cytochrome P450 Enzymes ◽  
Metabolizing Enzymes ◽  
Medical Interventions ◽  
Exogenous Agents ◽  
Health And Disease ◽  
Endogenous Substrates ◽  
Drug Metabolising Enzymes

Background: The biotransformation of xenobiotics is a homeostatic defensive response of the body against bioactive invaders. Xenobiotic metabolizing enzymes, important for the metabolism, elimination and detoxification of exogenous agents, are found in most tissues and organs and are distinguished into phase I and phase II enzymes, as well as phase III transporters. The cytochrome P450 superfamily of enzymes plays a major role in the biotransformation of most xenobiotics as well as in the metabolism of important endogenous substrates such as steroids and fatty acids. The activity and the potential toxicity of numerous drugs are strongly influenced by their biotransformation, mainly accomplished by the cytochrome P450 enzymes, one of the most versatile enzyme systems. Objective: In this review, considering the importance of drug metabolising enzymes in health and disease, some of our previous research results are presented, which, combined with newer findings, may assist in the elucidation of xenobiotic metabolism and in the development of more efficient drugs. Conclusion: Study of drug metabolism is of major importance for the development of drugs and provides insight into the control of human health. This review is an effort towards this direction and may find useful applications in related medical interventions or help in the development of more efficient drugs.

Pharmacogenomics of Cytochrome P450 Enzymes in Tumours

2004 ◽  
Vol 2 (3) ◽  
pp. 243-254 ◽  
Author(s):  
Diane Downie ◽  
Patrick Rooney ◽  
Morag McFadyen ◽  
Graeme Murray
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzymes
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