Metabolic stereoisomeric inversion of ibuprofen in mammals

doi:10.1016/0167-4838(91)90164-U

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology

Volume 1078, Issue 3, 12 July 1991, Pages 411-417

https://doi.org/10.1016/0167-4838(91)90164-U Get rights and content

Studies on the mechanism and enzymology of metabolic ibuprofen isomerization constituted the focus of this investigation. Comparative in vivo studies revealed that this biotransformation proceeded via a proton abstraction mechanism in all tested species of mammals, which is in agreement with the previous reports. Direct evidence supporting this conclusion stemmed from the in vitro epimerization of ibuprofen-CoA thioester in rat liver homogenates. Chemically synthesized (R)-ibuprofen-CoA thioester was rapidly transformed to its (S)-counterpart by subcellular hepatic preparations. Examination of this epimerase activity in various rat tissue homogenates indicated that this enzyme was highly tissue specific. This biochemical reaction mainly took place in the liver and kidney, whereas low levels of enzyme activity were associated with other tissues. Nevertheless, the liver and kidney homogenates failed to invert(R)-ibuprofen directly even in the presence of all the necessary cofactors. Presumably, the failure to characterize this bioconversion was due to the lack of enzymatic acyl-CoA synthesis in these homogenates. It is noteworthy that the ‘2-arylpropionyl-CoA epimerase’ catalyzed the transformation from either direction and with high turnover rates. The catalytic efficiency of (S)-ibuprofen CoA epimerization appeared to be greater than that of the (R)-counterpart. These in vitro findings suggest that the step of acyl-CoA formation assume a pivotal role in controlling the stereoselectivity and efficiency of the in vivo metabolism. As the responsible acyl-CoA synthetase(s) in different species of animals may exert the reaction with different degrees of enantiomeric preference and efficiency, the resulting stereochemical outcome and metabolic rates of this bioinversion vary accordingly. Consequently, in guinea pigs, this biotransformation proceeds in both directions with nearly equal efficiency, whereas it is virtually unidirectional and slow in humans. Currently, the purification and characterization of this novel ‘2-arylpropionyl-CoA epimerase’ from rat livers constitute the focus of this investigation.

References (30)

CaldwellJ. et al.
Biochem. Pharmacol.
(1988)
ChenC.-S. et al.
Biochim. Biophys. Acta
(1990)
GoldmanP. et al.
J. Biol. Chem.
(1961)
ProutyW.F. et al.
J. Biol. Chem.
(1972)
KornbergA. et al.
J. Biol. Chem.
(1953)
FournelS. et al.
Biochem. Pharmacol.
(1986)
WechterW.J. et al.
Biochem. Biophys. Res. Commun.
(1974)
KaiserD.G. et al.
J. Pharm. Sci.
(1976)
PandeS.V. et al.
J. Biol. Chem.
(1968)
PolokoffM.A. et al.
J. Biol. Chem.
(1977)

NormannP.T. et al.

Biochim. Biophys. Acta

(1981)

KnihinickiR.D. et al.

Biochem. Pharmacol.

(1989)

HuttA.J. et al.

J. Pharm. Pharmacol.

(1983)

MarascoW.A. et al.

Arch. Intern. Med.

(1987)

WheltonA. et al.

Ann. Intern. Med.

(1990)

Cited by (101)

Evaluation of the Stereochemical Lability of Benzo-Cycloheptene-Based Drugs Endowed with Potentially Modulable Planar Chirality
2023, European Journal of Organic Chemistry
An experimental and theoretical study was carried out to analyze the configurational lability possessed by some of the most common drugs endowed with a central non‐planar seven‐membered cycloheptadiene ring, which confers chirality to these compounds. In fact, the absence of planarity allows the existence of two enantiomeric species that can interconvert thanks to a ring overturning mechanism. The energy barrier that opposes the inversion of the chiral tricyclic scaffold characterizing such species, which is strongly dependent on the presence of appropriate substituents on the two external cycles, has been investigated through Dynamic‐HPLC and off‐column racemization techniques, as well as through assessments based on molecular modelling approaches. Interesting indications were obtained by making targeted structural changes to allow accurate control of the stereolability characterizing the tricyclic framework.
Extending the reach of computational approaches to model enzyme catalysis
2023, Bionanocatalysis: From Design to Applications
Chemical reactions are very useful for humankind because these reactions yield various products that are beneficial for them. To proceed these reactions fast, various catalysts are used. For each selective reaction, a selective catalyst is used. Chemoselectivity refers to those reactions that occur only at a specific functional group. Temperature plays a vital role in the occurring of chemical reactions. Arrhenius equation was introduced to describe reaction kinetics. The pictorial expression is used to show the concentration of reactants and products with the course of time. All enzymes are almost proteins, and by comparing the sequence of proteins, it is possible to determine their function and structure. Proteins are highly specific in their structure. If a single amino acid does not occupy its position, then it will be impossible for protein to execute its assigned task efficiently. Molecular simulations can be performed by using different ways such as MM and QM methods.
By the addition of enzyme computational stimulations, the protein design toolbox has been greatly improved. Not only do they warrant a more ambitious and through exploration of sequence space, but a much higher number of variants and protein–ligand systems can be analyzed in silico compared with experimental engineering methods. To redesign and for de novo generation of enzymes, modern computational tools are being used. These approaches are conditional on a deep understanding of the reaction mechanism and the enzyme's three-dimensional structure coordinates, but the wealth of information produced by these analyses leads to greatly improved or even totally new types of catalysis.
Pharmacology of Analgesics
2023, Anesthesia and Analgesia in Laboratory Animals
Pain management for laboratory animals is critical to assure the welfare of the animals and to minimize the confounding effects of pain on research results. There are three main types of pain: nociceptive pain, inflammatory pain and pathologic pain. Nociceptive and inflammatory pain provide a protective role. Nociceptive pain is a high-threshold pain used to sense noxious stimuli to prevent tissue damage. Inflammatory pain is initiated by the immune response to tissue damage. Pathologic pain results from abnormal nervous system responses or disease state. This chapter reviews the physiological mechanism of pain, the analgesic mechanism of action, pharmacology, clinical application and adverse effects of five main groups of analgesic drugs used in pain management: (1) nonsteroidal anti-inflammatory drugs (NSAIDs), (2) opioids, (3) α₂-adrenergic agonists, (4) NMDA-receptor antagonists, and (5) gabapentanoids.
Stereoisomers in sports drug testing: Analytical strategies and applications
2022, Journal of Chromatography A
Citation Excerpt :
For example, it was shown, that for some drugs already the albumin binding tendency or selected hepatic enzymes inhibited resp. accelerated the racemization significantly [38–40]. In contrast, for the other chiral anabolic agent zilpaterol, the published analytical data in the context of doping controls is scarce and enantiomeric information is entirely missing to date.
Analytics employed in modern doping controls are designed to cover an extensive range of rather diverse classes of substances, all of which are banned in sport according to the list of prohibited substances and methods of doping, resulting from their potential to be performance-enhancing and/or harmful to health. Many of these bioactive substances or their metabolites are chiral, which are comprehensively characterized and, if appropriate analytical approaches are applied, can be clearly identified. In sports drug testing, the enantiomeric composition of relevant compounds is not considered in all instances, although differences of isomers concerning their biological activity have been established. To date, the separation of stereoisomers in doping controls is only applied for selected target compounds, but with the development of efficient chiral chromatographic stationary phases, the added value of information on e.g. racemic shifts during the metabolic biotransformation reactions of drugs has been recognized. The immense variability of the substance classes represents however a major challenge, especially because both ‘classic’ doping agents belonging to the category of lower molecular mass molecules (e.g. stimulants, β₂-agonists, betablockers, corticoids, etc.) as well as larger molecules from the category of peptides and proteins necessitate consideration. In the present (mini)review, the current status of analytical techniques in the field of doping control analysis of stereoisomers is highlighted and critically reviewed.
Your mother was right, washing matters: An alkyne-analog of ibuprofen reveals unwanted reactivity of aromatic compounds with proteins during copper-catalyzed click chemistry
2021, Bioorganic and Medicinal Chemistry Letters
Bioorthogonal chemistry, in particular the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), has enabled the robust identification of covalent protein targets of probes and drugs. Ibuprofen is commonly used pain and fever reducer and is sold as an enantiomeric racemate. Interestingly, the stereoisomers can be enzymatically converted through an ibuprofen-CoA thioester intermediate, which might non-specifically react with protein nucleophiles. Here, we use an alkyne-analog of ibuprofen to make two discoveries. First, we find that ibuprofen likely does not result in notable chemical labeling of proteins. However, we secondly find that aromatic compounds can react with proteins during the CuAAC reaction unless they are appropriately washed out of the mixture. This second discovery of false positive labeling has important technical implications for the application of this approach.
An investigation of pregabalin lactamization process and effect of various pH on reaction: A computational insight
2020, Journal of Molecular Structure
Citation Excerpt :
These indicate the possible overlap between the nitrogen N11 and the carbon C1. So a lactamization reaction by an intramolecular attack by the nitrogen lone pair (N11) to carbonyl group carbon (C1) is highly possible [61]. As illustrated in Fig. 3, pregabalin can be degraded directly to prega-L.
The present work aims to provide a comprehensive insight into the lactamization reaction of pregabalin. Pregabalin which is an anticonvulsant drug can be degraded directly. This degradation reaction results in the generation of pregabalin lactam (prega-L) which is a highly toxic form. In this study, the geometry, energy landscape, kinetic and thermodynamic preference of this reaction were analyzed and investigated. The molecular dynamic (MD) simulations, density functional theory and the CBS-4M levels of theory were employed in order to carry out all the calculations. The lactamization reaction can be categorized as an intramolecular cyclization which after dehydration leads to the generation of pregabalin-lactam. The initial stage in this degradation reaction is the transformation of stable isomers into the unstable form, R∗. According to the calculations, there is a transition state close to the R∗. This transition state possesses 25.96 kcal/mol more energy than the ground state, R∗ (0.82 kcal/mol). Results of intrinsic reaction coordinates (IRC) calculations confirmed that this transition state ends up to pregabalin-lactam in one direction while it leads to the unstable R∗ in the other. Moreover, the values of energy were studied for both protonation and deprotonation forms of pregabalin to elucidate the role of different pH (acidic/basic) on this reaction. The obtained results confirmed that lactamization reaction depends on pH.

View all citing articles on Scopus

View full text

Metabolic stereoisomeric inversion of ibuprofen in mammals

Biochem. Pharmacol.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

J. Pharm. Sci.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochem. Pharmacol.

J. Pharm. Pharmacol.

Arch. Intern. Med.

Ann. Intern. Med.