A comprehensive review on medicinal plants possessing antioxidant potential.

Many research studies have proposed that about two-thirds of the medicinal plant species of the world possess significant antioxidant potential. Antioxidants are very beneficial as they decrease oxidative stress (OS) in cells and hence play their role in management as well as treatment of numerous diseases like cancers, cardiovascular diseases, as well as many inflammatory illnesses. This review comprises the antioxidant potential of numerous parts of medicinal plants like leaves, stems, roots, seeds, fruits, as well as bark. Synthetic antioxidants named butylated hydroxyanisole (BHA) as well as butylated hydroxytoluene (BHT) are extensively employed in foods because of their role as food preservatives. Several natural antioxidants have better efficacy as compared to synthetic antioxidants. These medicinal plants include Geranium sanguineum L., Rheum ribes L., Diospyros abyssinica, Sargentodoxa cuneata Rehd. Et Wils, Pistacia lentiscus, Ficus microcarpa L. fil., Polyalthia cerasoides (Roxb.) Bedd, Cunn, Teucrium polium L., Crataeva nurvala Buch-Ham., Urtica dioica L., Dracocephalum moldavica L., Momordica Charantia L., Acacia auriculiformis A., Bidens pilosa Linn. The Lamiaceae species, Radiata, Leea indica, Pelargonium endlicherianum, Salvia officinalis L., and Uncaria tomentosa (Willd.) DC. The literature study disclosed more side effects of synthetic antioxidants (including food additives) in comparison with natural antioxidants and for prevention of many diseases.

Endocrine Activity of AVB, 2MR, BHA, and Their Mixtures.

Personal care products are used increasingly, resulting in growing concern concerning their potential disruption of normal hormonal functions. Recent results on the bioaccumulation of cosmetic ingredients in wildlife and humans point to the need for an in-depth analysis for endocrine activity, in particular with respect to their influence on the androgen (AR), glucocorticoid (GR), and thyroid hormone receptors (TRs). Furthermore, humans are commonly exposed simultaneously to complex mixtures of endocrine active compounds. We have therefore examined 3 frequently used cosmetic ingredients: 2-methylresorcinol (2MR), butylated hydroxyanisole (BHA) and avobenzone (AVB), for (anti)-androgen-, (anti)-glucocorticoid-, and (anti)-thyroid hormone-like activities. Their binary and ternary mixtures at EC50 or IC50 concentrations have also been examined for anti-androgen-, glucocorticoid-, and thyroid hormone-like activities. In the MDA-kb2 reporter cell line, compounds possessed anti-androgen-, glucocorticoid-, and anti-glucocorticoid-like activities (except AVB). A new cell line, GH3.TRE-Luc, was used to evaluate anti-thyroid and thyroid hormone-like activities. The combinations 2MR + BHA and 2MR + BHA + AVB have glucocorticoid-like activity: only 2MR + AVB has anti-androgen-like activity. On the other hand, binary and ternary mixtures of compounds showed no thyroid hormone-like activity. Thus, in addition to identifying new endocrine disrupting compounds, it is also necessary to determine the effects of their mixtures in order to assess fully their risk to human health.

[Studies on estrogenic activities of food additives with human breast cancer MCF-7 cells and mechanism of estrogenicity by BHA and OPP].

Estrogenic activities of more than 90 chemicals including food additives, foodstuffs of plant origin, and some chemicals, which could be orally ingested, were examined by assaying estrogen receptor (ER)-dependent proliferation of MCF-7 cells. Among 66 food additives, 17 compounds stimulated the proliferation, but their concentrations giving maximal cell yield were higher than that of 17 beta-estradiol and their estrogenic activities were weak. Flavonoids had relatively strong estrogenic activities. In the assay of ER competitive binding to human ER alpha and ER beta in vitro, the antioxidant t-butylhydroxyanisole (BHA) had the capacity to compete with 17 beta-estradiol, while the capacity of o-phenyl phenol (OPP) was too small to calculate. Both BHA and OPP induced a decrease in gene expression of ER alpha and an increase in that of progesterone receptor in a time-dependent manner. These effects were similar to that of 17 beta-estradiol, a though much higher concentrations were required for these compounds than 17 beta-estradiol. These results may suggest that we should be careful not to ingest excessive food additives.

Intake of butylated hydroxyanisole and butylated hydroxytoluene and stomach cancer risk: results from analyses in the Netherlands Cohort Study.

Both carcinogenic and anticarcinogenic properties have been reported for the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). The association between dietary intake of BHA and BHT and stomach cancer risk was investigated in the Netherlands Cohort Study (NLCS) that started in 1986 among 120,852 men and women aged 55 to 69 years. A semi-quantitative food frequency questionnaire was used to assess food consumption. Information on BHA or BHT content of cooking fats, oils, mayonnaise and other creamy salad dressings and dried soups was obtained by chemical analysis, a Dutch database of food additives (ALBA) and the Dutch Compendium of Foods and Diet Products. After 6.3 years of follow-up, complete data on BHA and BHT intake of 192 incident stomach cancer cases and 2035 subcohort members were available for case-cohort analysis. Mean intake of BHA or BHT among subcohort members was 105 and 351 microg/day, respectively. For consumption of mayonnaise and other creamy salad dressings with BHA or BHT no association with stomach cancer risk was observed. A statistically non-significant decrease in stomach cancer risk was observed with increasing BHA and BHT intake [rate ratio (RR) highest/lowest intake of BHA = 0.57 (95% confidence interval (CI): 0.25-1.30] and BHT = 0.74 (95% CI: 0.38-1.43). In this study, no significant association with stomach cancer risk was found for usual intake of low levels of BHA and BHT.

Contact allergy to the monomers of p-tert-butylphenol-formaldehyde resin in the guinea pig.

In patients hypersensitive to p-tert-butylphenol-formaldehyde resin (PTBP-F-R), and butylphenol derivatives therein, it is for diagnostic, therapeutic and preventive reasons necessary to know the identity of the primary sensitizing substances, their sensitizing capacities as well as their cross-reaction patterns. The monomers in PTBP-F-R, 2-methylol p-tert-butylphenol (2-MPTBP) and 2,6-dimethylol p-tert-butylphenol (2,6-MPTBP), have been shown to be contact sensitizers in man. The aim of this study was to investigate the sensitizing capacities of the monomers and establish cross-reacting patterns in the guinea pig with the guinea pig maximization test. 2,6-MPTBP was shown to be a strong sensitizer while it was indicated that 2-MPTBP was a sensitizer. Animals sensitized to 2,6-MPTBP showed cross-reactions to 2-MPTBP and p-tert-butylcatechol. No cross-reactions were shown to p-tert-butylphenol, tert-butyl 4-hydroxyanisole (BHA) and 3,5-di-tert-butyl 4-hydroxytoluene (BHT).

Enhancement of the efficiency of photodynamic therapy of tumours by t-butyl-4-hydroxyanisole.

The effects of photodynamic therapy (PDT) alone and in combination with 3(2)-t-butyl-4-hydroxyanisole (BHA) on Ehrlich ascites carcinoma (EAC) cells have been investigated. BHA, a widely used food antioxidant, administered to the cells prior to light exposure is found to cause concentration-dependent alterations of the haematoporphyrin derivative (HpD)-based PDT. BHA (0.15 mM) causes a small (about 10%) inhibition in the rate of HpD-photosensitized injury of EAC cells. In contrast, upon increasing the concentration of BHA from 0.15 to 0.5 mM, a 1.3-fold enhancement in HpD-PDT efficiency is achieved. The cytotoxic effect on the cells treated with HpD-PDT and a higher concentration of BHA (0.5 mM) is additive. When BHA (0.5 mM) is given immediately after HpD-PDT, the combination is found to be three to four times more effective than when BHA is added to EAC cells before phototherapy. In this treatment regimen BHA acts synergistically with HpD-PDT. Such a difference in the action of BHA on the efficiency of HpD-PDT might be explained by the ability of BHA to inhibit the HpD-photosensitized destruction of some biomolecules. An enhancing action of BHA on the intensity of HpD-photosensitized death of tumour cells is also observed in vivo. Even a single dose of BHA (0.6 mM kg-1, 15 min after irradiation) causes (in an additive manner) an approximately two-fold increase in the efficiency of HpD-PDT of mice bearing Ehrlich ascites tumour (intraperitoneal transplantation). The results obtained indicate that the potentiating effect of BHA on the HpD-PDT could be caused by the impairment of the mitochondrial respiration, since there is a good correspondence between the concentration of BHA that increases the efficiency of PDT and the concentration that inhibits the oxygen consumption and dehydrogenase activity of EAC cells. The influence of BHA on the efficiency of PDT does not depend on the nature of the photosensitizer used; the effects with chlorin-e6 trimethyl ester are similar to that seen for HpD.

Augmentation of chrysotile-induced oxidative stress by BHA in mice lungs.

Asbestos is known to induce oxidative stress in the lung. The consumption of butylated hydroxyanisole (BHA) in preserved food and soft drinks is increasing in the general population, which includes workers in asbestos factories. Because there is no information on the effect of co-exposure to chrysotile and BHA, the time-dependent effects of a single intratracheal dose of chrysotile (1 mg per mouse) and a single ip dose of BHA (350 mg/kg body weight) on various indices of oxidative stress such as lipid peroxidation, hydrogen peroxide generation, glutathione peroxidase (GPX), glutathione reductase (GR), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione (GSH) were followed for up to 14 days. Microsomal lipid peroxidation (as well as that induced by NADPH) was significantly enhanced by BHA in the chrysotile-exposed group. GPX and GR activities in the same group were gradually decreased by BHA. Non-significant modulation of catalase activity by BHA was also noted. BHA induces GSH to a significant extent in lungs exposed with chrysotile. An increase in the G6PDH activity was maximal (19%; P < 0.05) at day 3. The results clearly demonstrate that BHA enhances chrysotile-induced oxidative stress in the lung.

Mechanism-based cancer risk assessment of butylated hydroxyanisole.

The evidence for BHA-induced carcinogenicity is restricted to the rodent non-glandular stomach, which is not found in humans. Although an argument can be made that an effect in this target organ could be indicative of potential carcinogenicity in other tissues, particularly the esophagus, studies have not revealed such a correlation. BHA-induced proliferative effects, which appear to be critical for the tumorigenic response, show a NOEL at a dose below that yielding benign tumors. The NOEL of this BHA-induced proliferative effect demonstrates a substantial margin of safety compared to human intake of BHA. Thus based on both dose-response considerations and the species-specific response, the use of BHA as a food additive does not pose a carcinogenic risk in humans.

Butylated hydroxyanisole in perspective.

Butylated hydroxyanisole (BHA) is a synthetic food antioxidant used to prevent oils, fats and shortenings from oxidative deterioration and rancidity. This review depicts the current knowledge on BHA. The physical and chemical characteristics of BHA are summarized and its function as a food antioxidant is made clear. The toxicological characteristics of BHA and its metabolic fate in man and animal are briefly reviewed. Special emphasis is laid on the carcinogenicity of BHA in the forestomach of rodents and to related events in the forestomach and other tissues in experimental animals. At present there is sufficient evidence for carcinogenicity of BHA, but there is hardly any indication that BHA is genotoxic. Therefore risk assessment for this epigenetic carcinogen is based on non-stochastic principles. However, the mechanism underlying the tumorigenicity of BHA is not known. In the last part of this review an attempt is made to unravel the unknown mechanism of carcinogenicity. It is hypothesized that BHA gives rise to tumor formation in rodent forestomach by inducing heritable changes in DNA. Evidence is being provided that reactive oxygen species, in particular hydroxylradicals, may play a crucial role. The key question with respect to risk assessment for BHA is whether or not the underlying mechanism is thresholded, which is important for the choice of the appropriate model to assess the risk, if any, for man and to manage any potential risk.

Allergic contact dermatitis to two antioxidants in latex gloves: 4,4'-thiobis(6-tert-butyl-meta-cresol) (Lowinox 44S36) and butylhydroxyanisole. Allergen alternatives for glove-allergic patients.

Allergic contact dermatitis developed on the hands and/or face of two patients after exposure to latex examination gloves. Both patients were patch test negative to the usual rubber allergens, but both had a positive patch test reaction to 4,4'-thiobis(6-tert-butyl-m-cresol) (Lowinox 44S36). Patient 2 was also patch test positive to butylhydroxyanisole. The patients were tested with other gloves, to find gloves that they could safely use. Glove manufacturers were queried to ascertain the occurrence of Lowinox 44S36 and butylhydroxyanisole in different brands of latex and vinyl examination gloves. A list of gloves and their associated allergens was generated and is provided to assist dermatologists in helping patients choose gloves free of specific allergens.

Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

Two patients with chronic idiopathic urticaria in whom remissions were achieved with dye- and preservative-elimination diet had exacerbations of their urticaria when they were challenged under double-blind, placebo-controlled conditions with butylated hydroxyanisole and butylated hydroxytoluene. After elimination of butylated hydroxyanisole and butylated hydroxytoluene from their diets, there was marked abatement of the frequency, severity, and duration of their urticaria. These antioxidants appear capable of aggravating symptoms in certain patients with chronic urticaria.

Cytotoxic effects of food additives and pharmaceuticals on cells in culture as determined with the neutral red assay.

The acute cytotoxicity of butylated hydroxytoluene and butylated hydroxyanisole to cultured human dermal fibroblasts, keratinocytes, melanocytes, and melanoma tumor cells was determined with the neutral red assay. For all cell types, butylated hydroxytoluene proved to be more cytotoxic than butylated hydroxyanisole. The neutral red assay is a rapid, economical, semiautomated assay that can be used with a variety of cell types in culture to provide quantitated data that can be used to rank test agents according to their potencies.