Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor.

[Alchemica]

Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor.

 

Monoamine oxidases inhibitors (MAOIs) are effective therapeutic drugs for managing Parkinson's disease (PD) and depression. However, their irreversibility may lead to rare but serious side effects. As finding safer and reversible MAOIs is our target, we characterized the recombinant human (h) MAO-A and MAO-B inhibition potentials of two common natural isoflavones, genistein (GST) and daidzein (DZ) using luminescence assay. The results obtained showed that DZ exhibits partial to no inhibition of the isozymes examined while GST inhibited hMAO-B (IC50 of 6.81 μM), and its hMAO-A inhibition was more potent than the standard deprenyl. Furthermore, the reversibility, mode of inhibition kinetics, and tyramine oxidation of GST were examined. GST was a time-independent reversible and competitive hMAO-A and hMAO-B inhibitor with a lower K i of hMAO-B (1.45 μM) than hMAO-A (4.31 μM). GST also inhibited hMAO-B tyramine oxidation and hydrogen peroxide production more than hMAO-A. Docking studies conducted indicated that the GST reversibility and hMAO-B selectivity of inhibition may relate to C5-OH effects on its orientation and its interactions with the threonine 201 residue of the active site. It was concluded from this study that the natural product GST has competitive and reversible MAOs inhibitions and may be recommended for further investigations as a useful therapeutic agent for Parkinson's disease.

"Flavonoids as chromone-containing polyphenolic structures are well-known natural antioxidant agents that may affect the catecholamine synthesis [17, 18]. Apigenin, luteolin, and quercetin are examples of flavonoids with potent MAO inhibitory activities [19]. The flavonoids subclass isoflavones, in particular, were an interesting investigational class of compounds in the last two decades due to their presence in medicinal and nutritional traditional plants.

 

Genistein (GST) and daidzein (DZ) are two isoflavone analogs naturally found in traditionally used medicinal plants such as bakuchi, soybeans, and red clover [20–22]. Previously, both analogs showed different activities on distinct MAOs sources; DZ showed no significant rat MAO inhibition [23] while GST showed a weak bovine plasma MAO inhibition [24]. In our search for natural MAOIs, GST and DZ were investigated for recombinant human MAO isozymes (hMAO-A and hMAO- inhibition with the objective to understand the mechanism of action and structure-activity relationship. By choosing these two structurally close compounds (natural chemical analogs), any difference in their inhibitory activity can disclose the structure-activity relationship between the extra GST functional group and the MAO-A or MAO-B inhibitions. Comparing another compound (e.g., DZ metabolite s-equol) with GST will not enable us to make a clear conclusion. Ultimately, the current study investigates the possibility of identifying safer and reversible natural MAO inhibitors for the possible therapeutic use in the management of PD."

"The determination of the proper dosage in patients to achieve MAOs inhibitory concentrations of GST based on the current in vitro study needs more research at the basic and the clinical levels. Considerations of GST metabolism and pharmacokinetics should be taken. In a clinical investigation using oral GST to manage postmenopausal osteoporosis in women, a dose of 54 mg/day was needed to achieve a steady-state level up to 1.00 μM [48]. We believe that the required dose of GST to achieve adequate therapeutic MOA inhibition might be less than the extrapolated dose available in the literature for three reasons. Firstly, GST was reported to be metabolized to its precursor biochanin A by intracellular enzymes [49, 50]. In our laboratory, we have found that biochanin A is more potent and selective hMAO-BI with an IC50 of 0.09 μM and an hMAO-A IC50 of 3.4 μM (Zarmouh et al., data to be published). Secondly, the dose of GST can be more than 54 mg/day as reported in a clinical trial in elderly [51]. Thus, both GST and metabolites may reach their target in the brain. Thirdly, we compared the MAOI of GST to DEP that needs higher doses for MAO inhibition. DEP was first investigated as an antidepressant but was not used because of its low bioavailability and the need for high oral doses as an MAO-AI [52] (greater than GST). DEP low bioavailability is mainly due to its high first-pass metabolism to amphetamine metabolites [6]. Nonetheless, DEP was formulated for skin delivery as DEP (Emsam) and, consequently, became a well-established effective MAOI used for depression in the elderly as a transdermal patch. This route of administration allowed higher bioavailability and also fewer restrictions on diet [53]. Similarly, GST bioavailability could be improved using the transdermal patch. Therefore, clinical and pharmacokinetic parameters investigations are needed to search for the best GST preparations or route of administration to achieve effective therapeutic concentrations in the brain for MAOs inhibition."

"The obtained results indicate that the isoflavone GST has potent hMAO-A and hMAO-B inhibitory activities compared to its analog DZ negligible inhibitory effects. GST MAO-A inhibition potency was more than the standard DEP. However, its affinity and potency to inhibit hMAO-B were higher than hMAO-A. GST valuable MAO inhibitory capacity over DZ and selectivity to inhibit MAO-B may be due to the presence of C5-OH substitution that may have worked as an inhibitory group. The data obtained clearly show that GST is a reversible and competitive MAO-A and MAO-B inhibitor and, consequently, can safely decrease hMAOs toxic H2O2 byproduct, with the least chance to have the cheese effect incidence. Based on the data obtained in this study we recommend further investigations to examine the use of GST as a possible agent for the therapeutic management of PD patients with depression."

[stonewolf]

Saying something exhibits more maoi a inhibition than selegiline isn't saying much.  If anything this would be negative as it would increase the risk of adverse food reactions.  I know reversible is the point but still.

 

If this is being explored for Parkinson's then shouldnt the study be far more concerned about the ability of these flavanoids to inhibit mao b ?  I mean it said it had a higher affinity for mao b over a but there is no scale.  A direct comparison for its ability to inhibit mao b vs selegiline would be nice.

 

I skimmed through though so please point out if i missed something.

 

 

[Alchemica]

 

Saying something exhibits more maoi a inhibition than selegiline isn't saying much.  If anything this would be negative as it would increase the risk of adverse food reactions.  I know reversible is the point but still.

 

If this is being explored for Parkinson's then shouldnt the study be far more concerned about the ability of these flavanoids to inhibit mao b ?  I mean it said it had a higher affinity for mao b over a but there is no scale.  A direct comparison for its ability to inhibit mao b vs selegiline would be nice.

 

I skimmed through though so please point out if i missed something.

 

 

You make good points.

 

Sure, more MAO-A inhibition than selegiline doesn't say much but I'm more interested in this study as it might (re)open up people's interest in using flavonoids as MAOIs.

 

Ki of hMAO-B (1.45 μM) than hMAO-A (4.31 μM) vs selegiline which has Ki values of 376+/-0.032 and 16.8+/-0.1 nM for MAO-A and MAO-B, respectively [1].

 

MAO-B inhibition is the primary concern for PD but the article also mentions depression so I'm guessing that's where the interest in MAO-A inhibition comes in.

 

Thanks for your interest.

Edited April 29, 2016 by Alchemica