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 Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Debendranath Dey ◽  
Sunetra Chaskar ◽  
Nitin Athavale ◽  
Deepa Chitre
Keyword(s):  
Cytochrome P450 ◽  
Radioligand Binding ◽  
Curcuma Longa ◽  
Raw 264.7 Cells ◽  
Cytochrome P450 Enzyme ◽  
Sprague Dawley ◽  
Cytochrome P450 Enzymes ◽  
Boswellia Serrata ◽  
Cell Counts ◽  
Anti Inflammatory

Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation ofWithania somnifera, Boswellia serrata, Zingiber officinale,andCurcuma longa,inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.

Theoretical insights into the reductive metabolism of CCl4 by cytochrome P450 enzymes and the CCl4-dependent suicidal inactivation of P450

2014 ◽  
Vol 43 (39) ◽  
pp. 14833-14840 ◽  
Author(s):  
Xiao-Xi Li ◽  
Qing-Chuan Zheng ◽  
Yong Wang ◽  
Hong-Xing Zhang
Keyword(s):  
Cytochrome P450 ◽  
Reduction Product ◽  
Cytochrome P450 Enzymes ◽  
Electron Reduction ◽  
The One ◽  
Reductive Metabolism

The one-electron reduction product, ˙CCl3, irreversibly inactivates P450 via covalently binding to the meso-carbon, whereas the two successive one-electron reductions product, :CCl2, reversibly inhibits P450 by coordinating to iron.

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.

scholarly journals Substrate-induced modulation of protein-protein interactions within human mitochondrial cytochrome P450-dependent system

2020 ◽  
Author(s):  
E.O. Yablokov ◽  
T.A. Sushko ◽  
L.A. Kaluzhskiy ◽  
A.A Kavaleuski ◽  
Y.V. Mezentsev ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Steroid Hormones ◽  
Protein Interactions ◽  
Fold Increase ◽  
Cytochrome P450 Enzymes ◽  
Protein Protein Interactions ◽  
Adrenal Steroid ◽  
Hormone Biosynthesis ◽  
Multiple Levels ◽  
And Function

AbstractSteroidogenesis is strictly regulated at multiple levels, as produced steroid hormones are crucial to maintain physiological functions. Cytochrome P450 enzymes are key players in adrenal steroid hormone biosynthesis and function within short redox-chains in mitochondria and endoplasmic reticulum. However, mechanisms regulating supply of reducing equivalents in the mitochondrial CYP-dependent system are not fully understood. In the present work, we aimed to estimate how the specific steroids, substrates, intermediates and products of multistep reactions modulate protein-protein interactions between adrenodoxin (Adx) and mitochondrial CYP11s. Using the SPR technology we determined that steroid substrates affect affinity and stability of CYP11s – Adx complexes in an isoform-specific mode. In particular, cholesterol induces a 4-fold increase in the rate of CYP11A1 – Adx complex formation without significant effect on dissociation (koff decreased ~1.5-fold), overall increasing complex affinity. At the same time steroid substrates decrease the affinity of both CYP11B1 – Adx and CYP11B2 – Adx complexes, predominantly reducing their stability (4-7 fold). This finding reveals differentiation of protein-protein interactions within the mitochondrial pool of CYPs, which have the same electron donor. The regulation of electron supply by the substrates might affect the overall steroid hormones production. Our experimental data provide further insight into protein-protein interactions within CYP-dependent redox chains involved in steroidogenesis.

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