Are Aloe Vera Vitamins Absorbed Through The Skin
J Environ Sci Wellness C Environ Carcinog Ecotoxicol Rev. Author manuscript; available in PMC 2019 January 28.
Published in terminal edited form every bit:
PMCID: PMC6349368
NIHMSID: NIHMS1001951
Aloe vera: A review of toxicity and agin clinical furnishings
Abstract
The Aloe plant is employed as a dietary supplement in a variety of foods and as an ingredient in cosmetic products. The widespread human exposure and its potential toxic and carcinogenic activities enhance rubber concerns. Chemical assay reveals that the Aloe found contains diverse polysaccharides and phenolic chemicals, notably anthraquinones. Ingestion of Aloe preparations is associated with diarrhea, hypokalemia, pseudomelanosis coli, kidney failure, also as phototoxicity and hypersensitive reactions. Recently, Aloe vera whole leafage extract showed clear bear witness of carcinogenic activity in rats, and was classified by the International Bureau for Research on Cancer as a possible human carcinogen (Group 2B). This review presents updated data on the toxicological furnishings, including the cytotoxicity, genotoxicity, carcinogenicity, and adverse clinical furnishings of Aloe vera whole leafage extract, gel, and latex.
Keywords: Aloe gel, aloe latex, Aloe vera, carcinogenicity, genotoxicity, toxicological effects
1. Introduction
The use of herbal products has been growing rapidly in the general population. In 2007, the National Health Interview Survey reported that approximately 40% of Americans, including adults and children, used complementary and alternative medicine as alternative therapy in the past 12 months.[1] About US $14.8 billion was spent on the purchase of nonvitamin, nonmineral natural products, which accounted for 44% of all out-of-pocket costs for complementary and alternative medicine.[2] Aloe has enjoyed a long history of providing a myriad of wellness benefits, and is one of the nearly ofttimes used herbal remedies employed throughout the world. There are more than 400 species of Aloe, but the most popular and widely used species is Aloe barbadensis Miller (also called Aloe vera Linne, commonly referred to Aloe vera). Aloe is derived from the Arabic give-and-take alloeh meaning "biting and shiny substance," and vera from the Latin word for "truth." Other species used in health and medicine include but are not limited to Aloe arborescens Miller (a member of the asphodelacea family), Aloeperryi Baker, Aloe andongensis, and Aloe ferox. [3,4]
Aloe vera, a genus within the Liliaceae family, is a stemless or very short-stemmed perennial succulent or xerophyte with elongated and peaked leaves in which big amounts of water are stored in the tissue.[five] The green fleshy leaves range in height from a few centimeters to ii-iii meters or more and accept iii identifiable layers. The outer layer is a thick cuticle or rind accounting for about 20%−thirty% by weight of the whole plant foliage. Information technology consists of upto eighteen layers of cells interspersed with chloroplasts where carbohydrates, fats, and proteins are synthesized. The outer leaf pulp, a thin, pasty layer just beneath and adjacent to the thick rind, contains vascular bundles acting as the transport system for the plants. Three types of tubular structures etch the vascular bundles: xylem, which moves water and minerals from the roots to the leaves; phloem, which takes synthesized minerals to the roots; and the pericyclic tubule, which stores and transports bitter yellowish latex (frequently referred to equally Aloe sap) along the margin of the leaf. The number of these bundles varies based on the size of leaves.[six] The inner leaf pulp makes up the majority of the constitute by volume, and is composed of big sparse-walled parenchymal cells containing Aloe vera gel, a synonym to inner leaf, inner leaf fillet, or fillet.
Aloe contains pharmacologically active ingredients associated with various biological activities including fungicidal, antiviral, antibacterial, anti-inflammatory, antimicrobial, laxative, immunomodulating, and anticancer effects.[3] Aloe vera, known as the "plant of immortality" in early Egypt, has been used as a traditional medicine in Arab, Chinese, Egyptian, Greek, Indian, Japanese, Korean, and Roman cultures[vii,8] for more than 2000 years to empirically treat a broad list of disorders and ailments, such as peel bug (wounds, x-ray and radium burns, and psoriasis), constipation, external and internal ulcers, hyperlipidemia, diabetes, and lupus erythematosus.[9-12] Due to the numerous purported benign effects, Aloe vera product has been an emerging industry for making laxative drugs, cosmetics, and functional food, such as face and manus creams, foundations, cleansers, lipsticks, suntan lotions, shampoos and hair tonics, shaving preparations, bath aids, makeup and fragrance preparations, baby lotions and wipes, yogurt, drinks, capsules, and tablets. In guild to evidence current pharmacological and/or toxicological inquiry status on Aloe, nosotros performed a literature search in PubMed using "Aloe" and specific country names as primal words (Table i). A total of 1895 and 975 publications were identified when using "Aloe" as key discussion in All Fields Not Author and MeSH term databases, respectively. More than half (51%−60%) of these studies were conducted in the summit 10 countries (Table i), and nigh one third of them are from five Asian countries, including People's republic of china, Bharat, Japan, Korea, and Iran. However, merely about 8% of these articles investigated Aloe-related toxicity in vitro and in vivo (Table 1).
Table 1.
Pharmacological and/or toxicological enquiry on Aloe based on PubMed online search.*
| Country | All fields# | MeSH term | ||
|---|---|---|---|---|
| | ||||
| Aloe | All | 1895 | 975 | |
| Cathay | 267 | 76 | ||
| India | 191 | 90 | ||
| USA | 188 | 95 | ||
| Japan | 110 | 61 | ||
| S Africa | 93 | 47 | ||
| Korea | 72 | 44 | ||
| Iran | 65 | 22 | ||
| Italy | 55 | 22 | ||
| UK | 48 | 21 | ||
| Brazil | 39 | 21 | ||
| Top ten countries | 1128 (60%) | 499 (51%) | ||
| Toxicity-related | 150 (8%) | 81 (viii%) | ||
Although Aloe vera has long been considered as a safe functional food material that can be used orally and topically,[13] on many occasions information technology has not been equally safe as normally thought. Recently, the reported adverse effects in humans and toxicity, genotoxicity, and carcinogenicity in both in vitro and in vivo studies enhance questions as to whether the components in Aloe vera may have tumor-promoting activities in humans. Due to its widespread human exposure and concerns that some components may crusade cancer, in 1998 the National Cancer Institute nominated Aloe vera equally a high-priority candidate for a carcinogenicity report under the National Toxicology Program (NTP). In 2002, the The states Food and Drug Administration (FDA) issued a final rule stating that use of Aloe as a nonprescription laxative drug is no longer generally recognized as safe and constructive.[14] Recently, Aloe vera whole foliage extract has been classified by the International Bureau for Research on Cancer as a possible human being carcinogen (Group 2B), along with other natural products such every bit Ginkgo biloba excerpt and kava extract.[15,16]
The Aloe vera whole leafage extract, too every bit the two master components (the gel and the latex or exudates) of the leafage, accept been used for various reasons in traditional medicine. By and large, the gel is used topically to soothe wounds, burns, and peel irritations, and the latex is recognized to possess cathartic effects. Even so, there is still some confusion surrounding the whole leafage extract, the gel, and the latex. Given that the beneficial properties of Aloe vera have been addressed comprehensively and that the gel and the latex possess distinct components and medical purposes,[5] in this commodity, the whole leaf extract, the gel, and the latex associated toxicity, genotoxicity, and carcinogenicity both in vitro and in vivo are reviewed, and adverse clinical effects in humans are besides summarized.
2.Aloe vera whole foliage extract
2.1. Components
Aloe vera whole foliage extract, including the gel and the latex, contains more 200 chemic substances.[4] The raw Aloe leaf is composed of approximately 98.5% water, the remaining solid textile contains a range of compounds including nutrients (e.k., carbohydrates, amino acids, vitamins, and minerals) and not-nutrients (e.g., organic acids, lignins, phenolic compounds, anthraquinones, and phytosterols). The chemical composition and the potency of the diverse constituents are influenced by many factors, such as species/subspecies, climate, state and irrigation, cultivation methods, harvesting, extraction processing, and storage conditions.[4,five]
To decide whether the presence of the latex alters the physical and chemic properties in whole leaf excerpt, the decolorized Aloe vera whole foliage has been studied for its toxicity and potential carcinogenicity. The decolorized excerpt was prepared by activated carbon-adsorption of the whole leafage extract (1%, west/w) to remove the latex portion of the plant, mainly anthraquinones, the components giving Aloe vera its laxative backdrop. Nevertheless, some of the high molecular weight polysaccharides of the inner leaf Aloe gel can also be removed by charcoal assimilation. Chemical analysis revealed that the concentrations of aloin, the principle anthraquinone of Aloe vera latex, differed by a factor of 100 in unfiltered and filtered extracts (8 mg/g for whole extract and 0.08 mg/yard for decolorized extract).[17] The loftier-performance liquid chromatography (HPLC) analysis showed large differences between the two extracts (Fig. i), indicating that the activated carbon-filtration eliminated a large number of components from the extract.[18] In addition, Aloe vera decolorized leaf excerpt exhibited a reduction in rheological values and approximately 19%−23% lower content of complex polysaccharides than either the gel or whole extract.[5]
Representative reversed-phase HPLC profiles of Aloevera whole leafage extract and decolorized whole leaf excerpt. V mg/ml samples were dissolved in Fischer's medium with pH adjusted to seven.0-7.2. HPLC analysis was performed using a Phenomenex Prodigy five μmODS column (4.6 mm ten 250 mm) eluted with methanol with a linear slope of 20%−60% h2o over xxx min and lx-100% methanol over 30 min at a flow charge per unit of one ml/min.
2.ii. Toxicity, genotoxicity, and carcinogenicity
2.two.1. Toxicity of the whole foliage extract
Logarto Parra and colleagues[nineteen] investigated the toxicity of Aloe vera (L.) Burm. F. (Aloeaceae) extract using both in vitro and in vivo assays. Xx-four hours following an acute oral exposure to Aloe vera dried leaf excerpt, the medium lethal concentration (LC50) in brine shrimp was estimated as 3.59 μg/ml and the lethal dose (LDl) in Swiss albino mice was 120.65 mg/kg. Another acute toxicity study demonstrated a maximum tolerated dose of 100 mg/kg torso weight and LD50 of 250 mg/kg, when the whole Aloe vera plant powder was extracted with 50% ethanol and administered intraperitoneally to developed albino mice at an initial dose of 400 to 500 mg/kg.[twenty] In addition, Aloe vera whole-leafage material caused a dose-dependent subtract in the viability in HeLa and HepG2 cells with half-maximal cytotoxic concentration (CC50) values of 413.9 and 439.0 mg/ml, respectively, post-obit a iv-h handling.[21] Information technology as well caused a dose-dependent increase of apoptosis in HeLa cells at concentrations up to m mg/ml.
In a subchronic toxicity study, 88 Sprague Dawley rats were fed Aloe whole foliage pulverisation at doses of 2, four, and 8 k/kg body weight (2.5%, 5%, and 10% Aloe in nutrition) for 90 days.[22] All dosed rats increased defecation and rats treated with the high doses as well showed reduced food efficiency and body weight. Relative kidney weight was significantly increased in males exposed to 8 one thousand/kg torso weight and all dosed females. All of the exposed groups displayed a pregnant increase in the incidences of pigmentation in renal tubular, mesenteric lymph nodes and lamina propria of the colonic mucosa, and proliferation in mesenteric lymph nodes. Reproductive toxicity was observed afterward a chronic oral ingestion of 100 mg/kg Aloe vera excerpt per solar day, which is one-5th of the pharmacologically active dose, for a period of 3 months.[23] This was manifested by meaning sperm impairment, hematological changes, inflammation, and bloodshed as compared to control animals.
Every bit part of a fourteen-solar day drinking water study conducted past the NTP, Aloe vera nondecolorized whole leaf excerpt and decolorized extract were administered to groups of iv male person and four female F344/Northward rats and the same numbers of B6C3F1 mice at 7 weeks of age.[24] The malic acid content of 0.5%−3% Aloe vera whole and decolorized extract solutions was 970-5820 μg/m and 1240-7440 μg/k water, respectively, and aloin A content was 70-422 μg/k and 0.8-four.5 μg/thou water, respectively. After 14 days female rats exposed to 1.5%—three% of decolorized extract displayed significantly decreased blood urea nitrogen levels, whereas rats exposed to 3% whole extract displayed reduced body weight, h2o consumption, gastrointestinal tract transit times, and liver, heart, spleen, thymus, and kidney weight than those of controls. Leukocyte and erythrocyte counts and hematocrit percentages were significantly elevated in both male person and female rats. In contrast, only a pregnant increase in water consumption was observed in female mice that received 2.0% nondecolorized whole extract.[24]
In comparison to this study, a highly purified decolorized whole foliage Aloe vera (L.) Burm. f. juice (full anthraquinones < 0.ane parts per million) was administered to F344/Du rats via drinking water at concentrations up to 2% (w/v).[25] This study was designed to compare the results obtained from other in vivo studies using whole leaf excerpt, specifically the NTP written report reported by Boudreau and colleagues.[24] No significant toxicological findings were observed subsequently subchronic exposure for 13 weeks. A similar written report besides showed no toxicity in F344 rats later on oral administration of a commercially available Aloe vera decolorized extract beverage up to 13 weeks, every bit evaluated past beliefs, stools, weight gain, feed consumption, organ weights, and intestinal mucosal morphologies.[26] These results suggest that anthraquinones may be a major contributor or serve every bit a marking of other agent(south) for Aloe vera-induced agin effects.[25]
two.two.2. Genotoxicity of the whole leaf excerpt
The genotoxicity of water extracted Aloe ferox was studied using the Bacillus sub-tilis rec-analysis in the 1980s. Aloe ferox is a palm-like succulent with many abrupt blood-red-brown spines on the margins of the leaves, giving the institute proper name "ferox" that means "vehement" or "war-like" in Latin. In the absence of metabolic activation, the lengths of inhibition zones formed by 6 mg of Aloe extraction on Rec+ and Rec- strains deviated distinctly from those of negative control samples, indicating a positive response in the Bacillus subtilis spore rec-assay.[27] However, no genotoxic furnishings were observed in the histidine reversion Ames test and DNA repair assays using Aloe vera decolorized extract beverage at up to 21 × concentrations.[26]
Recently, Aloe vera whole extract- and decolorized extract-induced cytotoxicity and genotoxicity were evaluated in our laboratory using the mouse lymphoma analysis (MLA).[18] This report used the same exam articles that were used for the 14-day studies by the NTP.[24] Afterward a 24-h treatment, both extracts exhibited concentration- dependent cytotoxicity and mutagenicity in the mouse lymphoma cells, with whole excerpt showing a positive response at lower concentrations than the decolorized extract. Molecular analysis of induced mutant colonies revealed that 77%−92% of the large colonies and 100% of the modest colonies from both treatments lost heterozygosity at the Tk locus and about half of the mutants lost heterozygosity at both the Tk and D11Mit42 loci, thus affecting approximately half-dozen-xxx centimorgans of the chromosome (Fig. ii). These results bespeak that the main type of harm from both treatments was large chromosome mutations (deletions and/or mitotic recombination). In addition, intracellular reactive oxygen species (ROS) levels induced by decolorized extract was nigh three-fold higher than that of whole extract in treated cells, suggesting that during the process of activated carbon filtration, some mutagenic components were removed from whole extract and other components with pro-oxidative or mutagenic activities, or both, might be enriched. Another important finding in this study was that the mutagenicity of the decolorized extract was detected at doses of well-nigh twice that required for whole excerpt-induced mutagenicity. Since the anthraquinone content was reduced by 99% in the decolorized extract relative to the whole extract, these results indicate that anthraquinones are non the merely mutagenic component of these mixtures and Aloe-induced genotoxicity may non be eradicated completely by removing these chemicals from Aloe preparations.[18]
Comparing of the percent of mutational types for all (large and small) colonies produced in cells treated with Aloe vera. Mouse lymphoma cells were treated for 24 h with iv.5 or v mg/ml whole leafage extract, or eight mg/ml decolorized extract. Whole excerpt at 4.5 or v mg/ml or decolorized extract vs control, p < 0.0001; 4.five mg/ml whole excerpt vs decolorized excerpt, p = 0.03; 4.five mg/ml vs 5 mg/ml whole extract, p = 0.37; 5 mg/ml whole excerpt vs decolorized extract, p = 0.26. Data from Tabular array iii in [18].
2.2.iii. Carcinogenicity of the whole leaf extract
NTP Technical Report 577 described clear evidence of carcinogenic action in F344/Due north rats after oral administration of Aloe vera whole leaf excerpt in drinking h2o for two years.[28] In this report, F344/North rats and B6C3F1 mice were exposed to 0%, i%, ii%, or iii% (wt/wt) excerpt for a catamenia of 13 weeks or 2 years. The 13-calendar week exposure acquired increased incidences of goblet jail cell hyperplasia in the large intestine of both rats and mice when compared to the control. The two-year study demonstrated significant dose-related increases in the incidences of adenomas and/or carcinomas of the ileocecal and cecal-colic junction, cecum, and the ascending and transverse colon in male and female rats in the high-dose groups.[28] Whole extract-induced big intestinal tumors in F344 rats and homo colorectal cancers shared similar changes in morphology and in molecular pathways, such every bit MAPK, WNT, and TGF-β signaling.[29] In a one-year report using Wistar Hannover rats, 4% Aloe arborescens (whole leaf powder extract) in the nutrition resulted in diarrhea, reduced body weight proceeds, yellowish pigmentation of ileocecal lymph nodes and renal tubules and astringent sinus dilatation of the ileocecal lymph nodes.[30] In the subsequent two-year report, adenomas or adenocarcinomas in the cecum, colon, and rectum were observed in the 4% male group, and adenomas were observed in the 4% female grouping. The irritation of the intestinal tract may contribute to the equivocal carcinogenic potential in the colon.[31] Due to the potential phototoxicity of herbal products,[32] Aloe whole leaf or decolorized whole foliage creams was applied topically in male and female SKH-1 hairless mice for one year.[33] Both products showed a weak enhancing effect on the photocarcinogenic activity of faux solar light, every bit manifested by significantly increased histopathologically-determined squamous cell neoplasm in some mice.
two.three. Adverse clinical effects of the whole leaf extract in humans
Topical and oral utilise of Aloe vera can crusade skin irritation, hives, cramping, and diarrhea to those who are allergic to other plants in the lily family unit, for example, onion and tulips. Several case reports on toxicity or hypersensitivity of Aloe products in humans are available, only at that place are no published controlled toxicology stud- ies.[34] A 35-year-quondam adult female experienced massive intraoperative bleeding subsequently oral consumption of Aloe vera tablets for two weeks earlier the surgery for leg pain. Compounds independent within Aloe vera can reduce the synthesis of prostaglandin, thus inhibiting secondary aggregation of platelets. Sevoflurane, a general anesthetic, inhibits thromboxane A(2) formation by suppressing cyclooxygenase activeness. Since both sevoflurane and Aloe vera take antiplatelet effects, the bleeding could accept been due to a possible herb-drug interaction between Aloe vera and sevoflurane.[35] A 47-twelvemonth-old man developed acute oliguric renal failure and liver dysfunction after ingestion of Cape Aloes, a previously described nephrotoxin.[36]
Hepatotoxicity is considered ane of the virtually reported adverse effects caused by herbal dietary supplements.[37] The first example of acute hepatitis due to the ingestion of Aloe vera compound was reported in 2005 in Germany.[38] After, cases of Aloe-induced toxic hepatitis were reported in Turkey,[39] United States,[40] Argentine republic,[41], and Korea.[42] A total of six females and 2 males were admitted to hospital for acute hepatitis after taking Aloe grooming over iii-260 weeks.[43] Their clinical manifestation, liver biopsy, and laboratory findings supported the diagnosis of toxic hepatitis. All viii patients showed improved weather condition later discontinuing this medication. These cases emphasize the importance of considering phytophar- maceutical over-the-counter drugs equally causative agents in hepatotoxicity.
iii.Aloe vera latex or exudate
3.1. Components
Aloe vera latex or exudate is distributed within vascular bundles located between the found'due south outer skin (rind) and the lurid. The pericyclic tubules, 1 of the three types of tubular structures of vascular bundles, store and transport Aloe vera latex forth the margin of the leaf. The latex is yellowish-brown in color and has a bitter gustation. Virtually 80 chemic constituents have been isolated past liquid chromatography in the latex, and most of the compounds are phenolic in nature, mainly anthraquinone C- glycosides, anthrones, and free anthraquinones.[44,45] Barbaloin, also known as aloin A, is identified as the major constituent in the latex.[5,46] The other three primary components are isobarbaloin (aloin B), aloesin (aloeresin B), and aloeresin A.[47] The latex likewise contains several other anthraquinones/anthrones and chromones including aloe-emodin, aloeresin E, aloenin,[44] likewise equally some aromatic compounds, for example, aldehydes (butanal, pentanal, etc.) and ketones (2-butanone, 2-heptanone, etc.).[47]
3.2. Toxicity, genotoxicity, and carcinogenicity
Aloe vera latex contains a number of biologically agile compounds, notably anthraquinones. Diverse in vitro and in vivo assays have been performed to evaluate the cytotoxicity, genotoxicity, and carcinogenicity of the chemical components contained within the latex, most especially aloe-emodin, aloin, emodin, and dan- thron.
iii.2.1. Toxicity of the latex
The cytotoxicity of aloe-emodin has been investigated intensively. Aloe-emodin induced apoptosis through various mechanisms, including a p53-dependent pathway in T24 human float cancer cells[48] and G2/G cell cycle arrest in human being promyelocytic leukemia HL-sixty cells.[49] During the apoptosis process induced by aloe-emodin and emodin in human lung squamous carcinoma cells (CH27) and human lung nonsmall jail cell carcinoma cells (H460), increases in cytosolic cytochrome c, caspase-three activation, and changes of protein kinase c (PKC) isozymes were observed.[50] This written report likewise demonstrated that PKC stimulation occurred at a site downstream of caspase-3 in the emodin-mediated apoptotic pathway. Another study demonstrated that aloe-emodine significantly inhibited proliferation and induced apoptosis in adult man keratinocytes.[51] The damage of ker- atinocyte proliferation could be observed at concentrations far below the industry standards for commercial products containing Aloe excerpt.
The toxicity of aloin was evaluated in human Jurkat T lymphocytes using flow cytometry and microscopy.[52] Aloin treatment resulted in decreased cell size, increased granularity, a block at the G2/One thousand phase of the prison cell bicycle, and loss of both membrane integrity and mitochondrial membrane potential in a dose-dependent manner, suggesting a mitochondrial-dependent pathway for aloin-induced apoptosis. UP780, a standardized composition of aloe chromone aloesin formulated with an Aloe vera inner foliage fillet, showed a no-observed-adverse-upshot-level in CD-ane mice with oral assistants of UP780 at doses of 2 g/kg/d for xiv days or upwardly to 1 g/kg/d for ninety days.[53]
3.ii.2. Genotoxicity of the latex
The genotoxicity of some anthraquinones has been confirmed in a variety of in vitro and in vivo analysis systems. A high proportion of anthraquinones was reported to be mutagenic in a number of strains of Salmonella typhimurium, for example, TA1537, TA1538, TA102, and TA98.[54-56] These strains are particularly sensitive to frameshift mutagens. Danthron and aloe-emodin were positive in strain TA1357 both with and without metabolic activation.[55] Aloe-emodin also induced increased revertant colonies in strains TA 1537, TA 1538, and TA 98.[57] Muller and colleagues[58] investigated the genotoxicity of 3 anthraquinones, emodin, danthron, and aloe-emodin using the MLA, micronucleus test, and the Comet analysis. At micromolar concentrations, all 3 compounds induced concentration- dependent increases in micronuclei and moderate increases in mutant frequency in L5178Y cells. Danthron and aloe-emodin also increased Deoxyribonucleic acid breaks at a concentration of 50 μM in the Comet analysis. The genotoxicity and mutagenicity induced past these anthraquinones were due to the inhibition of the catalytic activity of topoisomerase Two (Topo Two), with danthron being the about stiff.[58,59] Emodin, the least potent compound amongst the three anthraqinones, caused Dna doublestrand breaks past stabilizing Topo Ii-Deoxyribonucleic acid cleavage complexes and past inhibiting ATP hydrolysis of Topo II.[60] Aloe-emodin caused DNA damage in human lung carcinoma cells through the production of ROS,[61] induced micronuclei in TK6 human lymphoblastoid cells,[56] and chromosomal aberration in Chinese hamster ovary cells.[57] Danthron caused Dna harm and caspase cascade-mediated apoptosis in SNU-1 human gastric cancer cells through mitochondrial permeability transition pores and Bax-triggered pathways.[62]
An in vivo mouse Comet assay was performed on isolated kidney and colon cells of male OF1 mice in guild to demonstrate the possible organospecific genotoxicity of aloe-emodin.[56] Increases in DNA strand breaks in both the kidney and the colon were observed between 3 h and 6 h subsequently 2 oral administrations at 500,grand, and 2000 mg/kg body weight, suggesting an in vivo genotoxic mechanism of action.
3.ii.3. Carcinogenicity of the latex
Tumor promotion activities, such equally stimulation of cell proliferation and enhancement of malignant transformation, have been investigated in mice for 9 hydroxyan- thraquinones (HA) including danthron, aloe-emodin, and emodin.[63] A 2 to 3-fold increment in DNA synthesis was constitute in main rat hepatocytes exposed to danthron and aloe-emodin; and danthron also enhanced malignant transformation of C3H/M2 mouse fibroblasts pretreated with N-methyl-North'-nitro-Northward-nitrosoguanidine or 3-methylcholanthrene, suggesting that HA with hydroxy groups in the i,8- positions may take tumor-promoting activity. The carcinogenic potential of HA also has been demonstrated in a grouping of 29 male ACI/Due north rats.[64] After 480 days feeding with i% of HA, 25 of 29 rats developed adenomas or adenocarcinomas in the cecum or upper portion of the colon; liver neoplasms (neoplastic nodules and hepatocellular carcinomas) were observed in 12 rats; and benign tummy tumors were observed in five animals. These findings strongly propose that HA is carcinogenic in rodents.
A two-year feeding study of emodin in male and female person F344/N rats and B6C3F1 mice showed equivocal testify of carcinogenic activity for emodin in female F344/N rats due to a marginal increase in the incidence of Zymbal's gland carcinoma and in male B6C3F1 mice based on a low incidence of renal tubule neoplasms.[65] In the rat study, diets containing 0, 280, 830, or 2500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or 1000 mg/kg to males and 120, 370, or 1100 mg/kg to females) were administered to 65 male person and 65 female rats for 105 weeks. Three Zymbal's gland carcinomas were diagnosed in female person rats exposed to 2500 ppm. In the mouse study, 60 male and female mice were fed diets containing 0-625 ppm (equivalent to average daily doses of approximately 15-70 mg/kg) or 0-1250 ppm (equivalent to average daily doses of approximately thirty-120 mg/kg) emodin, respectively, for 105 weeks. Low incidences of renal tubule adenoma and one carcinoma each in the 312 and 625 ppm groups were observed in exposed male mice. No show of carcinogenic activity of emodin was found in female B6C3F1 mice even at the highest dose of 1250 ppm.
Evidence for aloe-emodin photocarcinogenicity was found in C3H mice afterward combined handling with ultraviolet radiation and aloe-emodin in ethanol vehi- cle.[66] C3H/HeN mice were treated with aloe-emodin in 25% ethanol topically iii times per calendar week for two weeks and exposed to 15 kJ/thousand2 UVB (280-320 nm) radiation. Primary cutaneous melanin-containing tumors were diagnosed in 50%−67% of the UV-irradiated mice given aloe-emodin in ethanol vehicle and in 20%−30% of the mice treated with a combination of UV radiation and ethanol vehicle, whereas no pare tumors were induced by aloe-emodin alone in the absence of UV radiation.
3.three. Adverse clinical furnishings of the latex in humans
The purgative effect of Aloe latex has long been recognized and has been used empirically to salve constipation. The earliest medical author to record the therapeutic use of Aloe is Dioscorides, a Greek doc of the first century A.D.[67] Subsequently, Aloe latex was used widely in herbal laxative preparations in many countries. Thus, a number of adverse effects resulting from ingestion of latex accept been reported in clinical studies. Prolonged employ was associated with electrolyte imbalance due to diarrhea, abdominal pain, vomiting, hypokalemia, pseudomelanosis coli, and the development of a cathartic colon—the colon becomes atonic and dilated. Longterm use of anthranoid laxatives might be correlated with the risk of developing colon cancer.[68]
A case of Aloe-induced Henoch-Schonlein purpura, an idiopathic vasculitis of the small vessels, was reported. A 52-year-old male patient from Pakistan presented astringent arthralgia, palpable purpura, and abdominal pain 10 days afterwards taking some juice extracted from four to five leaflets of Aloe vera. Xx-iv hours after the juice consumption, the human started to take rash on his legs and a balmy arthralgia of the talocrural joint. His symptoms worsened in the following days, and he developed diffuse, colicky, abdominal pain. Marked segmental necrosis and crescent formation were demonstrated by a renal biopsy. The renal dysfunction and nephritis were considered to be a consequence of big doses of Aloe.[69]
A 74-twelvemonth-old female presented with an impressive deep black pigmentation of the whole colon after chronic use of anthraquinone laxatives over many decades. Diverse adenomas, which were classified as precancerous lesions, were detected, but no colorectal carcinoma was establish.[70] An xviii-year-former Caucasian girl, who was treated with a combination laxative containing 5 ml danthron orally at night to meliorate constipation from 14 months one-time to 5-6 years erstwhile, presented a small bowel leiomyosarcoma with widespread dissemination.[71] Although one case cannot prove a causative clan betwixt danthron and the gamble of developing bowel cancer, the authors concluded that prolonged oral exposure to the laxative should be avoided in early childhood. In improver, pregnant women were advised not to take Aloe latex because its cathartic holding might result in stimulating uterine contractions, thereby increasing the risk for premature labor or miscarriage. Likewise, nursing mothers should not have laxatives because of the possibility of anthraquinones causing diarrhea in the infants.[3]
four.Aloe vera gel
4.1. Components
Aloe vera gel is a transparent mucilaginous jelly-like substance contained in the parenchymatous cells of fresh Aloe vera leaf pulp, with a gel yield of approximately 70% (70 m gel/100 g lurid) from the lurid by mechanical extrusion.[72] The gel has very loftier water content (99%−99.v%), with the remaining soluble solids making up 0.v%−1%,[73] and a range of gel acidity (pH) of iv.four-4.vii.[74] On a dry affair basis, the chemical constituents consist of 35% dietary fibers (nonstarch polysaccharides + lignin), 27% soluble sugars, 24% ash, and a pocket-sized fraction of lipids, proteins, enzymes, and mineral elements.[seven,72] The alcohol insoluble residues obtained from Aloe vera gel lyophilized fractions have a loftier content of carbohydrates (72%) including mannose, glucose, and uronic acids. Linear bondage of β−one-4-linked mannose and glucose molecules compose the principal polysaccharides at a ratio of 1~22:1 in the gel.[6,7,75-77] Almost investigators concord that acemannan, an acetylated glucomannan, makes up the major active component of the mucilaginous Aloe vera gel,[72] while others report pectic substance as the main polysaccharide.[73] The discrepancies are considered to be a result of differences in the species, seasons of the year, geographical locations, and the gel extraction procedure.
4.2. Toxicity, genotoxicity, and carcinogenicity
The toxic furnishings of Aloe vera gel have been reported only in a few studies. At that place is multifariousness in the results of the observed toxic furnishings which may exist largely due to the differences in the gel contents that are greatly influenced by a diverseness of factors including seasons, locations, irrigation, harvest time, and, most importantly, the lack of standardization of the gel preparations.
4.ii.1. Toxicity of the gel
The cytotoxicity of Aloe vera gel has been confirmed in monolayers of craven fibroblasts based on the observations of disrupted intercellular junctions and the formation of cell-costless gaps in the monolayers afterwards treatment.[78] The cell injury analysis was conducted using three fractions isolated from the Aloe barbadensis leaves, native gel (mucilaginous parenchymous tissue scraped from Aloe leaves), purified gel (the nondialyzable fraction of the native gel), and the low molecular weight fraction (LMWF, the dialyzable material). A 1:10 dilution of native gel and the LMWF promoted like cell injuries, while the purified gel behaved like the command at the same dilution. These severe cellular amercement were distinct enough to exist detected under a microscope. Therefore, it was proposed that the toxicity was mainly acquired by the LMWF from the gel since the beneficial characteristics were suggested to upshot from the loftier molecular weight components.[78] Following a four-hour treatment, an Aloe vera dehydrated gel material induced dose-dependent cytotoxicity in HeLa cells, with a CC5o value of 269.three mg/ml.[21]
Aloe vera gel was administered in drinking water to groups of four male and four female person F344/N rats in a 14-24-hour interval study conducted past the NTP.[28] The gel quality was monitored past the content of malic acrid and aloin A (barbaloin). Drinking water solutions of 0.5%−iii% Aloe vera gel contained 1060-6360 μthousand malic acid/yard water, and 5.half-dozen-33.3 μthou aloin A/g water. After the fourteen-day exposure, dose-related increases in urine glucose levels in female person rats and dose-related decreasing trends in serum levels of triglycerides, cholesterol, and albumin were observed at concentrations of ane.5% or greater in female person rats and of 3.0% in male rats. When adult male Wistar rats were orally administered with Aloe vera gel extract solution (150 and 300 mg/kg/day) for viii weeks, the weight of testes, serum testosterone, sperm count, and sperm fertility were significantly decreased compared to the command rats.[79] In another in vivo report using a commercial stabilized Aloe vera gel consumed as a beverage, no changes were found in feed consumption, torso weight gain, and serum chemical science tests post-obit a thirteen-week subchronic exposure in B6C3F1 mice.[80]
After five.5 months ingestion of crude skinned Aloe filet to male F344 rats, no adverse issue was observed on torso weight gain, food intake, gastrointestinal transit time, or gross pathology at dietary concentrations of 1% or 10% (respective to doses of Aloe vera gel of ~0.33 and 3.3 g/kg bw/24-hour interval).[16,81] Life-long ingestion of depression dose (1%) Aloe vera filet acquired no obvious harmful furnishings or deleterious changes in the rat.[82]
4.two.2. Genotoxicity of the gel
Studies on the biological effects of Aloe vera pulp excerpt on Escherichia coli-deficient repair mutants and plasmid DNA revealed genotoxic backdrop of the gel, simply non cytotoxicity because of the poor permeability through the cell membrane. The agarose gel electrophoresis assay showed that Aloe vera pulp excerpt produced dose- dependent unmarried-strand breaks in the plasmid Deoxyribonucleic acid.[83] In vitro and in vivo safety studies using a high-purity Aloe vera inner leaf fillet preparation demonstrated that the gel was nonmutagenic in the Ames test, the chromosomal aberration exam, and the in vivo bone marrow micronucleus test, following oral administration at doses up to five thousand/kg bw/twenty-four hour period to rats for 90 days[84] Similarly, a commercial gel juice did not induce a significant increase in SOS DNA repair in Escherichia coli or mutagenesis in Salmonella TA100[80]
iv.two.3. Carcinogenicity of the gel
No carcinogenicity data are bachelor for Aloe gel.
iv.3. Adverse clinical effects of the gel in humans
Aloe gels were first used clinically in the 1930s for the treatment of radiation burns.[34] Afterward, several clinical trials of Aloe vera gel have been carried out in the treatment of burn wounds,[85] oral lichen planus,[86] hyperlipidemic type 2 diabetic patients,[87] and recurrent aphthous stomatitis.[88] Merely some pocket-sized adverse effects were reported in these studies, such equally discomfort, pain, and the evolution of hypersensitive reactions. Nevertheless, generalized eczematous and papular dermatitis were found in a male person patient in response to the oral and topical apply of the Aloe vera gel.[89] Pruriginous erythema was observed on the legs and eyelids of a 72-year- one-time adult female later applying self-made Aloe vera leaf juice over the legs.[90] A very slow recovery from the dermatitis induced past Aloe vera preparations was reported in four cases after dermabrasion and chemic peel.[91] No severe adverse effects or carcinogenicity have been reported from using Aloe vera gel.
five. Perspectives
More than than 300 meg people worldwide consume dietary supplements and herbal plants, and near one-half of Americans use them regularly.[92] Dietary or herbal supplement products are expected to exist condom, effective, and of appropriate quality. Yet, the complex chemical nature of dietary supplements makes it difficult to evaluate their efficacy and safety. Herbal products often showroom great variability in quality because of some issues including authentication, adulteration and exchange, and factors during growth, harvest, and postharvest processing.[93] Hallmark of constitute species used for preparation of herbal dietary supplements is important for safety assurance. Too traditional approaches, the use of molecular/genetic profiling in identification of specific molecular changes (fingerprints) and in unveiling signature indicative of exposures remains a promising nevertheless still largely unexplored approach.[94,95]
The reported agin furnishings accept raised concerns of public health risks regarding the concentration, limerick, and private contaminants of dietary supplements. Herbal dietary supplements and other herbal products take been recognized every bit the common causes of drug-induced liver injury.[96] A recent report indicates that dietary/herbal supplements are implicated in 19% of drug-induced astute liver failure cases,[97] because consumers oft purchase these products online without the supervision of a health care provider and are non aware of drug-herb interactions and advisable warnings. A total of 1179 English language-language, herbal product- related websites (including retail and nonretail websites) were examined and only ~x% of them recommended consultation with a health care professional. In addition, simply about 8% of cyberspace retailers provided information on potential agin effects, drug interactions, and other bones condom precautions; and less than 3% cited scientific references to their claims.[98]
Aloe plant contains multiple constituents with potential benign and toxico- logical activities. Three distinct preparations derived from Aloe vera (i.e., the whole leaf extract, Aloe vera gel, and Aloe vera latex) have been used as topical and oral therapeutic remedies. The gel is primarily used topically for wounds and skin problems, as well as taken orally for the treatment of gastrointestinal ulcers and dia- betes.[9] The latex is regulated as a drug by the FDA to relieve constipation and the whole leaf extract may possess antibacterial/viral and anticancer activities.[5] Aloe vera appears to exist safe when used equally a flavoring in foods[16]; and the polysaccharide material derived from the inner gel is noncytotoxic as evaluated past the Cosmetic Ingredient Review Skilful Panel.[iii] Yet, due to the cytotoxicity, mutagenicity, and carcinogenicity of anthraquinones, it is crucial to monitor the content of these phenolic compounds in Aloe vera whole leaf extract and latex.[5,24] The International Aloe Science Council standard suggests that the maximum allowable aloin content in Aloe-derived fabric for oral consumption is less than 10 ppm (parts per one thousand thousand); for nonmedical use the recommended limit is 50 ppm or lower.[iii,99]
According to Multinational Integrated Information Assay conducted by IMS Health (Danbury, CT), the estimated global sales of Aloe products have reached Us $351 million.[16] Due to the increased popularity and utilization of Aloe plant, indepth studies are needed to investigate the agin effects, conventional drug interactions, and the possible toxic and carcinogenic effects of Aloe preparations, especially after long-term apply of these products.
Acknowledgments
We give thanks Drs. Robert H. Heflich, Page B. McKinzie, and Vasily N. Dobrovolsky for their helpful suggestions and comments. The information in these materials is not a formal dissemination of data past the US Food and Drug Administration and does not stand for agency position or policy.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349368/
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