In Silico Taste, Cytochrome and Toxicity Prediction Study of Major Chamomile Constituents

DOI: https://doi.org/10.53523/ijoirVol8I3ID106 Abstract Chamomile is an ancient herb used for various medications. It contains many bioactive constituents such as volatile oils, terpenoids, flavonoids, lactones, acid esters, glycosides and others. By reviewing many references, a confliction appeared of using Chamomile preparations to treat primary teeth eruption symptoms as a therapy administered by pediatric dentist or pediatrician. In this study, thirteen bioactive constituents (α-bisabolol (B), chamazulene (C), umbelliferone (U), apigenin (A), apigetrin (AT), apiin (AI), luteolin (L), quercetin (Q), quercimertrin (QT), rutin (R), α-cadinene (CD), α-farnesene (F), and matricarin (M) were subject to computational predication through various online websites to predicate their taste, activity towards several CYP450 enzymes and their action as Hepatotoxic, carcinogenic, immunotoxic, mutagenic, and cytotoxic compounds. Our calculations revealed several points such as high value of taste predication indicated that Chamomile constituents under study were with sour taste, did not classify as individual fatal compound Class (GHS) 1 or 2, 44.87% of them showed inhibition character toward specific cytochrome P450 enzyme while 43.59% were noninhibition character, more than (0.5) probability predication of various cytochrome P450 enzymes gave a positive activity that may affect liver functions. Also, hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity predictions were more than (0.5), unsaturated Chamomile constituent (Farnesene, F) had highest immune – and mutagenic properties whilst the disaccharide flavonoid (Rutin, R) had the highest Carcinoimmunogenic response. According to the above notes, our conclusion is to use minimum concentration of Chamomile preparation for less period of time and lowest repeating intake that ensure effective treatment of teething symptoms under supervision of pediatricians with minimum side effect.

Numerical Taste predication (Table (1      Cytochrome P450 family is a superfamily of terminal oxidase enzymes composed of protein with heme group as cofactor found in all living kingdoms. Its coded enzymes based electron transfer (oxidation -reduction) chain like CYP1A2, CYP2C9, CYP2C19, and others that induction, inhibition, and competition properties specify for example drug interaction. So, CYP1A2 (Cytochrome P450 1A2) is member of this oxidase system as monooxygenase to metabolize xenobiotic, drugs, endogenous materials in body and synthesize lipids, cholesterol, steroids. Also, CYP2C19 is another monooxygenase (epoxygenase) works as liver enzyme protein in catalysis of xenobiotic metabolism [10,11,12].
Cytochrome activity with tested constituents was studied with two online website http://insilicocyp.charite.de/SuperCYPsPred/ (Table (2)) and https://preadmet.bmdrc.kr/adme/ (Table (3)). According to Table  (2), the results were calculated by two methodologies: Molecular Access System MACCS ("166 bit-long structural key descriptor in which each bit is associated with a specific structural pattern") and Molecular fingerprint (Morgan). The maximum difference between both methods was 0.326. Cytochrome response varied between all tested constituents but in general showed highest inhibition value with CYP3A4 (Table 2, Figures (3 & 4)). Also, both MACCS and Morgan fingerprint showed approximately same sequence.
The other website that predicate cytochrome inhibition did not show numerical data and did not compatible in cytochrome types that been calculated (Table (3)). Figure (5) represents Table (3) results by replace inhibitor predication with 2, weakly with 1, non-inhibitor with 0 and substrate with 3.
It is a good notice that Chamomile constituents under predication (Table (4)) are not presented in Class 1 or 2 (the fatal category). The other very good sign in this Table (4) is most of these compounds may be harmful if swallowed. Class 4 had be characterized in B and C while Class 3 to Q and M. Also, U has Class 6 the safer class. From Table ( Hepatotoxicity sign caused by chemical is important in human health and drug industry and this acute liver damage sign is resulting by increasing level of specific enzyme [13,14]. M showed the lowest acute liver damage probability while AI was the highest with 0.85 Table (4) and Figure (6). The reason behind this increase of hepatotoxicity in AI is the presence of furanosyl and glucosyl moieties in the structure of this natural flavonoid (apigenin diglycosidyl flavone) resulting more oxygen atoms that increased interaction with liver active molecules compared to M.
When chemical inducing tumor after long time exposure and an accumulation in the target organ, this chemical identify as carcinogen and studying this sign requires inlife rat, mice, and then human testing of adsorption and metabolism [15,16,17]. Carcinogenic probability of γbutyl lactone M was 0.53 as the least value compared to 0.88 of the citrus disaccharide flavonoid R that as the highest potential hazard (Table (4) and Figure (6)).
Immunotoxicity character of any chemical is endpoint study of in Vitro, in Vivo and / or computational models and represents the correlation between this chemical and food and cellular actions [18,19]. Risk probability of immune system with C (bicyclic unsaturated hydrocarbon with aromatic character), A (flavonoid), R (flavonoid), or F (tetraene) was the highest compared with the lowest QT (flavonoid) as shown in Table ( Exposure of environmental species to hazard causing heritable change of DNA is Mutagenicity. This term of securing nucleotide sequence can be screened by in Vivo and computational methods to ensure quality of chemical upon living organisms [17,18,21,22,23]. Cytogenetic character of the semi-identical flavonoids L and Q was 0.51 while α-sesquiterpene isomer (F) showed the highest mutagenic predication response (0.98) (Table (4) and Figure (6)).
In vitro biocompatibility of a primary cell with chemical is a reflection of its function after this biological interaction [24,25]. Contrary to mutagenicity predication, the toxicity caused by the action of L and Q on living cell was 0.99 as the highest cytotoxicity compared to U and R with 0.68 in spite that Chamomile constituents (L, Q, U, and R) are flavonoids (Table (4) and Figure (6)).
It can be noticed from calculation that the unsaturated Chamomile constituent (F) had highest immuneand mutagenic properties. In addition, the disaccharide flavonoid (R) had the highest Carcino-immunogenic response.

Figure (6). Toxicity predication of Chamomile constituents under test.
By back to the confliction between a notice in a scientific reference concerned of herbal medicine [2] and other published articles [3][4][5][6] that in general confirmed using Chamomile preparations to treat primary teeth eruption symptoms as a therapy administered by pediatric dentist or pediatrician followed by antipyretic prescription [26], our calculations revealed several points:  High value of taste predication indicated that Chamomile constituents under study were with sour taste.  The studied compounds did not classify as individual fatal compound Class (GHS) 1 or 2.  44.87% of them showed inhibition character toward specific cytochrome P450 enzyme while 43.59% were non-inhibition character.  More than (0.5) probability predication of various cytochrome P450 enzymes gave a positive activity.  Hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity prediction probabilities were more than (0.5).  Unsaturated Chamomile constituent (Farnesene, F) had highest immuneand mutagenic properties.

Conclusions
Thirteen bioactive Chamomile constituents were studied with different online website to predicate their taste, activity towards several CYP450 enzymes and their action as Hepatotoxic, carcinogenic, immunotoxic, mutagenic, and cytotoxic compounds. The computational models in these online website showed that these 13 compounds were not fatal as GHS Classification. They had a noticeable inhibition activity against various CYP450 enzymes that may affect liver functions. In general, probable Hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity of them appeared especially Farnesene as the highest immun -mutagenic properties and Rutin as the highest Carcino-immunogenic response. According to the above notes, our conclusion is to use minimum concentration of Chamomile preparation for less period of time and lowest repeating intake that ensure effective treatment of teething symptoms under supervision of pediatricians with minimum side effect.