A Toxicological Evaluation of Methylliberine (Dynamine®).

Timothy S Murbach,Adél Vértesi,Ilona Pasics Szakonyiné,Gábor Hirka,Amy E Clewell,Erzsébet Béres,Róbert Glávits,John R Endres

doi:10.1155/2019/4981420

Timothy S Murbach, Adél Vértesi + Show 6 more

Open Access

https://doi.org/10.1155/2019/4981420

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Abstract

Methylliberine (CAS 51168-26-4), a methoxiuric acid, is a caffeine metabolite present at low levels in various Coffea plants; however, very little has been published regarding this compound and we could find no toxicological data in the public domain. Therefore, we undertook the toxicological investigation of a pure, synthetic form of methylliberine in order to evaluate its potential health hazards as a food ingredient. A (1) bacterial reverse mutation test, (2) in vitro mammalian chromosomal aberration test, (3) in vivo mammalian micronucleus test, and (4) 90-day repeated-dose oral toxicity study in rats with a 28-day recovery period were conducted. No in vitro mutagenic or clastogenic activity was observed in the presence or absence of metabolic activation up to the maximum OECD recommended test concentrations. No genotoxicity was observed in the mammalian micronucleus study up to the highest dose tested of 700 mg/kg bw. In the 90-day study, methylliberine was administered to Han:WIST rats at doses of 0, 75, 112, 150, 187, and 225 mg/kg bw/day. No mortality or morbidity was observed and no toxicologically relevant clinical effects or effects on clinical pathology parameters were observed. In male animals, test item-related effects on body weight and sexual organs, which were not reversible after a 28-day recovery period without treatment, were observed in the high-dose group. Body weight development was also slightly and reversibly depressed in the 187 mg/kg bw/day male group. No toxicological effects were observed in females. The NOAEL for females was determined to be 225 mg/kg bw/day, the highest dose tested, while the NOAEL for males was determined to be 150 mg/kg bw/day. Future studies are encouraged to corroborate the safety, and assess efficacy, of methylliberine in humans.

Highlights

In the current work we conducted a battery of toxicological investigations in order to evaluate the potential of methylliberine to cause genetic toxicity and possible health hazards likely to arise from repeated exposure of methylliberine and to estimate a no-observed-adverse-e ect level (NOAEL) in rats
E studies described were conducted in compliance with OECD Principles of Good Laboratory Practice (GLP) [6], except for the following deviation: analytical control of the test item formulations for homogeneity and stability was not performed because no appropriate test method has been validated
We have described the OECD methods and laboratory standard operating procedures (SOP) used in previous works [7,8,9,10,11,12], and summarize them again, in brief, below

Summary

Introduction

E slight structural di erences between theacrine and methylliberine have been hypothesized to result in slight di erences in the pharmacokinetic pro les of the two compounds, with methylliberine thought to have a shorter time to reach maximum plasma concentration and a shorter half-life with respect to theacrine. Because of these hypothetical properties, there is interest in methylliberine as an ingredient in functional foods and dietary supplements, and clinical trials to investigate all three hypotheses are currently underway.

Materials and Methods

In Vitro Mammalian Chromosomal Aberration

Results and Discussion

In Vitro Mammalian Chromosomal Aberration Test

In Vivo Mammalian Micronucleus Test

Conflicts of Interest