Compendio degli studi più significativi con riferimento a proprietà, assunzione, effetti.

Urbain P, Valverde J, Jakobsen J. Impact on Vitamin D2, Vitamin D4 and Agaritine in Agaricus bisporus Mushrooms after Artificial and Natural Solar UV Light Exposure. Plant Foods Hum Nutr. 2016 Sep;71(3):314-21. doi: 10.1007/s11130-016-0562-5. 

Abstract. Commercial mushroom production can expose mushrooms post-harvest to UV light for purposes of vitamin D2 enrichment by converting the naturally occurring provitamin D2 (ergosterol). The objectives of the present study were to artificially simulate solar UV-B doses occurring naturally in Central Europe and to investigate vitamin D2 and vitamin D4 production in sliced Agaricus bisporus (button mushrooms) and to analyse and compare the agaritine content of naturally and artificially UV-irradiated mushrooms. Agaritine was measured for safety aspects even though there is no rationale for a link between UV light exposure and agaritine content. The artificial UV-B dose of 0.53 J/cm(2) raised the vitamin D2 content to significantly (P < 0.001) higher levels of 67.1 ± 9.9 μg/g dry weight (DW) than sun exposure (3.9 ± 0.8 μg/g dry DW). We observed a positive correlation between vitamin D4 and vitamin D2 production (r(2) = 0.96, P < 0.001) after artificial UV irradiation, with vitamin D4 levels ranging from 0 to 20.9 μg/g DW. The agaritine content varied widely but remained within normal ranges in all samples. Irrespective of the irradiation source, agaritine dropped dramatically in conjunction with all UV-B doses both artificial and natural solar, probably due to its known instability. The biological action of vitamin D from UV-exposed mushrooms reflects the activity of these two major vitamin D analogues (D2, D4). Vitamin D4 should be analysed and agaritine disregarded in future studies of UV-exposed mushrooms.

Merdivan S, Willke C, Lindequist U. Development and Validation of an LC-MS/MS Method for the Quantification of Agaritine in Mushrooms. Int J Med Mushrooms. 2016;18(1):13-21. doi: 10.1615/IntJMedMushrooms.v18.i1.30. 

Abstract. Agaritine, an aromatic hydrazine, is found as a secondary metabolite in mushroom species. It is among others suspected to exhibit genotoxic activity. This publication describes the validation of a method for the quantification of agaritine in mushrooms (i.e., extraction and purification by solid phase extraction) and measurement by liquid chromatography with tandem mass spectrometry detection in positive ionization mode. The results show this method to be selective, accurate, and precise. This method could be used for the quality control of pharmaceutical preparations containing mushrooms.

Schulzova V, Hajslova J, Peroutka R, Hlavasek J, Gry J, Andersson HC. Agaritine content of 53 Agaricus species collected from nature. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2009 Jan;26(1):82-93. doi: 10.1080/02652030802039903. 

Abstract. Fifty-three different species of the genus Agaricus were collected in the Czech Republic during the period 1998-2001 and identified by an experienced mycologist. The samples were analysed for agaritine (N2-(gamma-L-glutamyl)-4-hydroxymethylphenylhydrazine) content, a precursor to a suspected rodent carcinogen. There was a huge variation in agaritine content between species, but less variation between samples of a species. Whereas the cultivated mushroom Agaricus bisporus commonly contain 200-500 mg agaritine kg(-1) fresh weight, no less than 24 of the 53 species contained agaritine levels above 1000 mg kg(-1) fresh weight. The highest level was found in A. elvensis containing up to 10, 000 mg kg(-1) fresh weight. Twenty species contained intermediate levels (100-1000 mg kg(-1)), and nine species were below 100 mg kg(-1). Some of the species producing low levels of agaritine might be candidates for future strain development of Agaricus mushrooms for cultivation. No correlation could be observed between agaritine content and size of the mushroom, week of the year when collected, year of collection, or site of collection. Besides occurring in the genus Agaricus, some species of the genera Leucoagaricus and Macrolepiota were also shown to contain agaritine.

Sommer I, Schwartz H, Solar S, Sontag G. Effect of gamma-irradiation on agaritine, gamma-glutaminyl-4-hydroxybenzene (GHB), antioxidant capacity, and total phenolic content of mushrooms ( Agaricus bisporus ). J Agric Food Chem. 2009 Jul 8;57(13):5790-4. doi: 10.1021/jf900993h. 

Abstract. Fresh mushrooms ( Agaricus bisporus ) were irradiated at doses of 1, 3, and 5 kGy to assess the effect of gamma-irradiation on the major aromatic compounds agaritine (beta-N-(gamma-L-(+)-glutamyl)-4-(hydroxymethyl)phenylhydrazine) and GHB (gamma-glutaminyl-4-hydroxybenzene) as well as on the total phenolic content and antioxidant capacity. Up to 3 kGy, agaritine was not affected. At 5 kGy, a significant reduction (p = 0.05) from 1.54 (0 kGy) to 1.35 g/kg dry weight (DW) was observed. gamma-Glutaminyl-4-hydroxybenzene decreased by 22% at 1 kGy and by 31% at 5 kGy. Additionally, agaritine standard solutions at concentrations of 10(-4) and 5 x 10(-5) mol/L were irradiated to compare the effect on agaritine content in aqueous solutions and in the sample matrix. A rapid decay was observed, 50% at 750 Gy (10(-4) mol/L) and 400 Gy (5 x 10(-5) mol/L). The total phenolic content and antioxidant capacity were not significantly (p = 0.05) influenced by irradiation.

Kondo K, Watanabe A, Akiyama H, Maitani T. The metabolisms of agaritine, a mushroom hydrazine in mice. Food Chem Toxicol. 2008 Mar;46(3):854-62. doi: 10.1016/j.fct.2007.10.022.

Abstract. The mushroom hydrazine agaritine was measured in mouse plasma and urine using LC/MS/MS, which is highly specific. Agaritine concentration peaked 20 min after oral administration to mice (4.0 and 40 mg/kg). The concentration gradually decreased and returned to the basal level in 100 min. The maximum concentration, the time to the maximum concentration, and the half life were 0.37 microg/ml plasma, 0.33 h, and 0.71 h, respectively after administration of agaritine at 40 mg/kg body weight. One agaritine metabolite was found in the plasma and the urine from agaritine-administered mice. The structure of metabolites of agaritine by gamma-GT was next investigated using LC/MS. HMPH proved to be generated from agaritine. The oxidative stress marker 8-OHdG was detected in agaritine-administered mouse urine. After administration, the 8-OHdG level immediately tripled, and then decreased to the control level over 48 h. Its level then elevated again and remained high for 11 days. These results suggest that agaritine quickly metabolizes and disappears in the plasma, whereas DNA damage lasts for a long time after a single administration of agaritine to mice.

Agaritina è una sostanza naturale, una molecola anfipatica (presenta sia un gruppo idrofobo che un gruppo idrofilo) e una genotossina che si trova in molti funghi di bosco della specie Agaricus, il fungo champignon ed in particolare in Agaricus blazei Murrill. È un derivato dell'idrazina ed è oggetto di ricerca per le sue potenziali implicazioni sulla salute.

Questo composto è un derivato dell'amminoacido glutammico e dell'ammina fenilidrazina.

• Acido glutammico. È un aminoacido, uno dei mattoni delle proteine. Svolge un ruolo chiave nel metabolismo cellulare ed è anche il precursore del neurotrasmettitore glutammato. Ha un gruppo carbossilico (-COOH) e un gruppo amminico (-NH2) attaccati a un atomo di carbonio, oltre a una catena laterale che contiene anch'essa un gruppo carbossilico.
• Fenilidrazina. È un composto organico costituito da un gruppo fenile (un anello di sei atomi di carbonio, noto anche come anello benzenico) collegato a un gruppo idrazina (-NH-NH2). La fenilidrazina deriva dall'idrazina e viene utilizzata nella sintesi chimica, in particolare nella sintesi di indoli e idrazoni.

Il procedimento di sintesi si svolge in diverse fasi:

• Formazione del derivato della fenilidrazina. La fenilidrazina viene modificata per formare un derivato che può reagire ulteriormente per produrre agaritina. Questa fase di modifica può comportare la funzionalizzazione della molecola di fenilidrazina attraverso reazioni come l'acilazione, l'alchilazione o altre trasformazioni chimiche.
• Glicosilazione. Il derivato di fenilidrazina modificato viene quindi sottoposto a glicosilazione, in cui una parte di zucchero viene attaccata alla molecola. Questa fase si ottiene in genere facendo reagire la fenilidrazina modificata con uno zucchero o un derivato di zucchero adatto.
• Depurazione. Il prodotto grezzo ottenuto dalla fase di glicosilazione è solitamente impuro e contiene altri sottoprodotti. Per isolare l'agaritina dalle impurità si possono utilizzare tecniche di purificazione come la cromatografia su colonna, la cristallizzazione o la ricristallizzazione.
• Caratterizzazione e analisi. Una volta purificata, l'agaritina sintetizzata deve essere caratterizzata e analizzata per confermarne la struttura chimica e la purezza. Per l'analisi strutturale si possono utilizzare tecniche come la risonanza magnetica nucleare (NMR), la spettrometria di massa (MS) e la spettroscopia infrarossa (IR).

L'agaritina si presenta in forma di polvere cristallina bianca o biancastra.

A cosa serve e dove si usa

Medicina

L'agaritina che è presente in Agaricus blazei induce moderatamente l'apoptosi nelle cellule leucemiche U937 (1),  e può essere considerato un candidato interessante per lo sviluppo di medicine anti HIV (2). Anche i beta-glucani, una classe di fibre polisaccaridi, presenti in questi funghi appartenenti alla famiglia dei Basidiomiceti, hanno dimostrato di agire come immunostimolanti contro le cellule tumorali (3).

Per questo composto chimico sono stati selezionati gli studi più rilevanti con una sintesi dei loro contenuti:

Agaritina studi

• Formula molecolare: C₁₂H₁₇N₃O₄ 
• Peso molecolare: 267.285 g/mol
• CAS: 2757-90-6
• EC Number: 
• UNII: UX8Y7QVP8M

Sinonimi: 

• beta-N-(gamma-L(+)Glutamyl)4-hydroxymethylphenylhydrazine
• L-Glutamic acid, 5-(2-(4-(hydroxymethyl)phenyl)hydrazide)
• Glutamic acid, 5-(2-(alpha-hydroxy-p-tolyl)hydrazide), L-
• beta-N-[gamma-l(+)-Glutamyl]-4-hydroxymethylphenylhydrazine
• L-Glutamic acid, 5-(2-(alpha-hydroxy-para-tolyl)hydrazide)
• L-Glutamic acid, 5-(2-(4-(hydroxymethyl)phenyl)hydrazide) (9CI)
• 2-[4-(hydroxymethyl)phenyl]-L-glutamohydrazide
• (2S)-2-amino-5-{2-[4-(hydroxymethyl)phenyl]hydrazino}-5-oxopentanoic acid
• beta-N-(alpha-L-Glutamyl)-4-hydroxymethylphenylhydrazine
• L-Glutamic acid,5-[2-[4-(hydroxymethyl)phenyl]hydrazide]
• 2-amino-5-{2-[4-(hydroxymethyl)phenyl]hydrazino}-5-oxopentanoic acid

Bibliografia__________________________________________________________

(1) Akiyama H, Endo M, Matsui T, Katsuda I, Emi N, Kawamoto Y, Koike T, Beppu H. Agaritine from Agaricus blazei Murrill induces apoptosis in the leukemic cell line U937. Biochim Biophys Acta. 2011 May;1810(5):519-25. doi: 10.1016/j.bbagen.2011.02.010. 

Endo M, Beppu H, Akiyama H, Wakamatsu K, Ito S, Kawamoto Y, Shimpo K, Sumiya T, Koike T, Matsui T. Agaritine purified from Agaricus blazei Murrill exerts anti-tumor activity against leukemic cells. Biochim Biophys Acta. 2010 Jul;1800(7):669-73. doi: 10.1016/j.bbagen.2010.03.016. 

(2) Gao WN, Wei DQ, Li Y, Gao H, Xu WR, Li AX, Chou KC. Agaritine and its derivatives are potential inhibitors against HIV proteases. Med Chem. 2007 May;3(3):221-6. doi: 10.2174/157340607780620644. 

Abstract. Agaritine, or beta-N-[gamma-L(+)-glutamyl]-4-hydroxymethylphenylhydrazine, is a Chinese herbal medicine, known having the antiviral and anticancer function. However, so far no reports whatsoever have been made for its potential as an anti-HIV agent. It was observed by docking experiments for more than 9,000 compounds extracted from various Chinese medicines that the compound agaritine distinguished itself from all the others in binding to the HIV protease with the most favorable free energy. Based on this, a series of derivatives were generated by modifying agaritine. It has been observed thru an extensive docking study that some of agaritine derivatives had markedly stronger binding interaction with the HIV protease than agaritine, suggesting that these derivatives might be good candidates for developing drugs for AIDS therapy.

(3) Bashir KMI, Choi JS. Clinical and Physiological Perspectives of β-Glucans: The Past, Present, and Future. Int J Mol Sci. 2017 Sep 5;18(9):1906. doi: 10.3390/ijms18091906. 

Abstract. β-Glucans are a group of biologically-active fibers or polysaccharides from natural sources with proven medical significance. β-Glucans are known to have antitumor, anti-inflammatory, anti-obesity, anti-allergic, anti-osteoporotic, and immunomodulating activities. β-Glucans are natural bioactive compounds and can be taken orally, as a food supplement, or as part of a daily diet, and are considered safe to use. The medical significance and efficiency of β-glucans are confirmed in vitro, as well as using animal- and human-based clinical studies. However, systematic study on the clinical and physiological significance of β-glucans is scarce. In this review, we not only discuss the clinical and physiological importance of β-glucans, we also compare their biological activities through the existing in vitro and animal-based in vivo studies. This review provides extensive data on the clinical study of β-glucans.