Rationale and Objectives
The observation that the intravenous application of gadolinium-based contrast media can lead to nephrogenic systemic fibrosis (NSF) has raised interest in their interactions with pathways. In this context, histamine is a focus because of its stimulating effect on fibrogenesis. In humans, histamine can be inactivated either by diamine oxidase (DAO) or by histamine N-methyltransferase (HMT), and numerous drugs are known to inhibit these enzymes. Therefore, it was the aim of this study to investigate whether magnetic resonance imaging contrast agents have an inhibitory effect on the enzymatic activities of DAO and HMT.
Materials and Methods
Seven gadolinium-based (gadoterate meglumine, gadoteridol, gadobutrol, gadobenate dimeglumine, gadopentetate dimeglumine, gadoxetate disodium, gadodiamide) and one manganese-containing (mangafodipir) contrast agents were tested in vitro. Following the preincubation of purified DAO and HMT with 0.1 to 10 mmol/L of the respective contrast medium, enzyme activities were determined using radiometric microassays. Enzyme activities measured in the absence of contrast agents and after preincubation with specific inhibitors of DAO and HMT, respectively, served as controls.
Results
The gadolinium-containing and manganese-containing contrast media tested did not show significant inhibition of the activities of DAO and HMT. No significant difference was observed between ionic and nonionic or between cyclic and linear gadolinium compounds. Preincubation of the enzymes with specific inhibitors led to complete inhibition of the respective enzymatic activity.
Conclusion
The gadolinium-containing and manganese-based magnetic resonance imaging contrast media tested did not exhibit significant inhibition of histamine-inactivating enzymes at physiologically relevant concentrations.
The intravenous application of gadolinium-containing or manganese-containing contrast media is widely used in magnetic resonance imaging (MRI). Currently, little is known about the biologic effects of these contrast agents, but since nephrogenic systemic fibrosis (NSF) was identified as a severe adverse reaction after intravenous application of gadolinium chelates, interest has been aroused in this field . In this context, it is an interesting question whether contrast media have an influence on enzymes, and recently, an up-regulation of transglutaminases has been reported .
Histamine acts as an inflammatory mediator, a neurotransmitter, and a regulator of hydrochloric acid secretion from gastric mucosa by binding to and activating four different histamine receptors . It has been proposed to play an important role in skin fibrosis because it stimulates fibroblast proliferation and collagen production . It has been shown that MRI contrast media can lead to increased histamine concentrations in cell cultures .
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Materials and methods
Contrast Agents
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Table 1
Properties of Radiographic Contrast Media Used for Inhibition Studies
Substance Brand Name Substance Group Structure_M_ (g/mol)c (g/L)C (mol/L) Gadoterate meglumine Dotarem ∗ Gadolinium based Cyclic, ionic 558 500 279 Gadoteridol ProHance † Gadolinium based Cyclic, nonionic 558 500 279 Gadobutrol Gadovist ‡ Gadolinium based Cyclic, nonionic 605 1000 605 Gadobenate dimeglumine MultiHance † Gadolinium based Linear, ionic 1058 500 529 Gadopentetate dimeglumine Magnevist ‡ Gadolinium based Linear, ionic 938 500 469 Gadoxetate disodium Primovist ‡ Gadolinium based Linear, ionic 726 250 181 Gadodiamide Omniscan § Gadolinium based Linear, nonionic 574 500 287 Mangafodipir Teslascan § Manganese based Linear, ionic 757 10 7.6
C , molar concentration of substance in commercial preparation; c , mass concentration of substance in commercial preparation; M , molecular weight of substance.
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Radiometric DAO Microassay
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Radiometric HMT Microassay
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Statistical Analyses
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Results
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Table 2
Enzymatic Activities of DAO and HMT After Incubation with 0.1 to 10 mmol/L of Manganese-based and Gadolinium-based Magnetic Resonance Imaging Contrast Media
DAO Activity (%) HMT Activity (%) Substance 0.1 mmol/L 1 mmol/L 10 mmol/L 0.1 mmol/L 1 mmol/L 10 mmol/L Control 100 100 Gadoterate meglumine 99 98 97 100 98 98 Gadoteridol 112 109 115 91 93 93 Gadobutrol 101 103 95 93 92 105 Gadobenate dimeglumine 95 94 94 95 99 106 Gadopentetate dimeglumine 96 96 95 95 95 103 Gadoxetate disodium 115 114 109 93 100 105 Gadodiamide 94 94 99 100 101 108 Mangafodipir 108 104 ND 102 99 ND 0.01 mmol/L 0.1 mmol/L 1 mmol/L 0.001 mmol/L 0.01 mmol/L 0.1 mmol/L Aminoguanidine 0 0 0 ND ND ND Amodiaquine ND ND ND 21 3 0
DAO, diamine oxidase; HMT, histamine N-methyltransferase; ND, not determined.
Activities were calculated relative to uninhibited controls treated identically but incubated without any additions (100%), which were 891 dpm corresponding to 81 μU for DAO and 2887 dpm corresponding to 28 μU for HMT, respectively. For positive inhibition controls, DAO was incubated with 0.01 to 1 mmol/L aminoguanidine and HMT with 0.001 to 0.1 mmol/L amodiaquine.
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Discussion
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