Accepted Manuscript

Pharmacokinetic and Toxicological Aspects of Potassium Sorbate Food Additive and

Its Constituents

Parvin Dehghan, Ali Mohammadi, Hossein Mohammadzadeh-Aghdash, Jafar Ezzati

Nazhad Dolatabadi

PII: S0924-2244(18)30005-0
DOI: 10.1016/j.tifs.2018.07.012
Reference: TIFS 2273

To appear in: Trends in Food Science & Technology

Received Date: 4 January 2018

Revised Date: 15 March 2018
Accepted Date: 12 July 2018

Please cite this article as: Dehghan, P., Mohammadi, A., Mohammadzadeh-Aghdash, H., Nazhad
Dolatabadi, J.E., Pharmacokinetic and Toxicological Aspects of Potassium Sorbate Food Additive and
Its Constituents, Trends in Food Science & Technology (2018), doi: 10.1016/j.tifs.2018.07.012.

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 ACCEPTED MANUSCRIPT

Pharmacokinetic and Toxicological Aspects of Potassium Sorbate Food

Additive and Its Constituents

Parvin Dehghana,1, Ali Mohammadib, Hossein Mohammadzadeh-Aghdashb,c,*,1, Jafar Ezzati

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Nazhad Dolatabadid,*,1
a
Department of Food Science and Technology, Faculty of Nutrition and Food Sciences, Nutrition

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Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
b
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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c
Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
d
Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz,

Iran.
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*Corresponding authors: Hossein Mohammadzadeh-Aghdash, E-mail:

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hosein.safety@gmail.com & Jafar Ezzati Nazhad Dolatabadi, E-mail: ezzatij@tbzmed.ac.ir, Tel:

+98 41 33367914, Fax: +98 4133367929.

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These authors contributed equally.

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Abstract

The synthetic food additives such as potassium sorbate (PS) are commonly used as a more

effective protectant in food and pharmaceutical industries. Recently, increased chronic diseases

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generated more concerns in consumers and government about preservatives. Regarding

contradictory results that has been attained via various studies on application of food additives,

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the exact monitoring of additives remains controversial by governments. Various research results

showed that the increased PS intake (>25mg/kg) may lead to cytotoxic and genotoxic effects via

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producing mutagenic compounds and inducing chromosome aberrations, sister chromatid

exchange, DNA breakage. The aforementioned factors can develop many chronic diseases

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especially diabetes mellitus, cancers and etc. Thus, it is necessary to investigate the effects of PS
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on public health and determin its mechanism of action on various organs and cells. Therefore,
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this article aimed to evaluate the PS safety through overview of its effects on various tissues,

cells and biological macromolecules.

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Keywords: Potassium sorbate; food additive; antimicrobial effects; pharmacokinetic; toxicity.

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Table of Contents

1. Introduction ................................................................................................................................. 3
2. Physio-chemical properties of potassium sorbate ....................................................................... 6
3. Analysis methods of potassium sorbate in food ......................................................................... 6

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4. Potassium sorbate as a food preservative.................................................................................... 7
4.1. Potassium sorbate reaction in food....................................................................................... 8
4.2. Antibacterial and antifungal properties of potassium sorbate .............................................. 9

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5. Metabolism and pharmacokinetics studies of sorbate .............................................................. 11
6. Toxicity and side effects of PS ................................................................................................. 13

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7. Conclusions ............................................................................................................................... 16
References ..................................................................................................................................... 17

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1. Introduction
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Consumers require safe food to supply the vital needs of their bodies and therefore, food
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products and its active ingredients have an important effect on nutrition and human health (Fathi,
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Mohammadzadeh-Aghdash, Sohrabi, Dehghan, & Dolatabadi, 2017; Mohammadzadeh-

Aghdash, Ezzati Nazhad Dolatabadi, Dehghan, Panahi-Azar, & Barzegar, 2017). Microbial
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contaminations have been considered as major hazards in terms of food safety. In this regard,

food spoilage has been a more important problem worldwide, and most of food spoilage
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occurrence during the shelf life of food is due to the activity of microorganisms or enzymatic
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reactions (Ezzati Nazhad Dolatabadi, et al., 2014; Hamishehkar, Khani, Kashanian, Ezzati

Nazhad Dolatabadi, & Eskandani, 2014; Türkoğlu, 2007). Approximately, one-third of the

people in developed countries suffer from food related illness. It has been evidenced that more

than 200 microbial, chemical, and physical agents are responsible for spreading these diseases. In

2011, the Center for Disease Control (CDC) in the USA estimated that 3,000 people annually die

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due to diseases transmitted through food and 128,000 people are hospitalized (Makwana,

Choudhary, Dogra, Kohli, & Haddock, 2014). The chemical compounds are mainly used to

prevent food spoilage and omit foodborne illness in animals and humans (Dolatabadi &

Kashanian, 2010; S. Kashanian & Dolatabadi, 2009; Sohrabi, Panahi-Azar, Ezzati Nazhad

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Dolatabadi, & Dehghan, 2017). Although chemical compounds can be most important part of the

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daily diet as effective food preservatives but their usage is restricted by US Food and Drug

Administration (FDA) due to food safety issues. Even though, some of these chemical

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preservatives did not show any significant effect on public health upon addition to food products,

however, most of them have important effect both at in vitro and in vivo investigation. Therefore,

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a few of these preservatives are approved for use in food products (Dolatabadi & Kashanian,
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2010; Eskandani, Hamishehkar, & Ezzati Nazhad Dolatabadi, 2014; Fathi, Ezzati Nazhad

Dolatanbadi, Rashidi, & Omidi, 2016; Soheila Kashanian & Ezzati Nazhad Dolatabadi, 2010).
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Potassium sorbate (PS; Fig. 1) has been used as a efficient preservative in food, cosmeceutical,
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and pharmaceutical industries and thus its safety on human must be considered (Taghavi, et al.,
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2013). Although this preservative legally used in foods but it can be harmful if its body uptake is

higher than the permitted limits. PS are widely used in protectant processed foods such as fruit
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juice, soda, soy sauce, ketchup etc. This additive inhibit mold growth, prevent spoilage and

preserve freshness of the products. This compound is one of the synthetic additive that can break
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down into sorbitol, potassium, and sorbic acid. PS is manufactured industrially via neutralizing
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the sorbic acid with potassium hydroxide (E Lück, Jager, & Nico Raczek, 2011). Sorbic acid

(C6H7O2) is a straight-chained monocarboxylic acid and naturally generated in various plants,

organism tissues and in fermented goods through microbial growth. Sorbic acid is found in

foods, animal feeds, pharmaceutical drugs, cosmetics, and unripened berries of the rowan tree

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i.e. Sorbus aucuparia (Additives, 2005). This substance was first extracted from Rowan fruit and

chemically is produced via a two-step process through the condensation of ketene and

crotonaldehyde. Since this material is generally recognized as safe (GRAS) in different countries

including the European Union and the USA, it can be used as antifungal and antimicrobial

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preservatives in variety of food, cosmeceutical, and pharmaceutical products (Amirpour, Arman,

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Yolmeh, Akbari Azam, & Moradi-Khatoonabadi, 2015; Silva & Lidon, 2016). The PS with the

natural pH of 4.5 is widely used as an effective preservative in the acidic foods against fungi,

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yeast, and bacteria. The antimicrobial activity of PS, sorbic acid and different preservative is due

to the presence of carboxyl group (-COOH) and the number of carbon atoms in their structure. It

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has been demonstrated that food additives with shorter carbon chains such as sodium acetate and
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PS have more antibacterial activity compared to additives with long carbon chains

(Mohammadzadeh-Aghdash, et al., 2018).

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Concentration of this material under legal limits is considered as a harmless substance by Good
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Manufacturing Practices (GMP). However, its side effects on public health has been previously
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demonstrated. Cytotoxic and genotoxic effects of PS via inducing chromosome aberrations,

sister chromatid exchange, DNA breakage has been reported. Also activation of inflammatory
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pathways via gene expression of NFκB, GADD45α, MAPK8 and induction of oxidative stress

due to advanced glycation end products (AGEs) activation, and other reactive carbonyl
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compounds such as oxidative glycated intermediate products with the ability to react with free
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amino groups of interaction with albumin was approved (Mamur, Yüzbaşıoğlu, Ünal, & Yılmaz,

2010; Yolmeh, Najafi, Farhoosh, & Salehi, 2014).

The aim of this article was to provide a multidisciplinary review about PS and sorbic acid

applications in foods products, their pharmacokinetic, and toxicological effects on public health.

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2. Physio-chemical properties of potassium sorbate

PS is a potassium salt of sorbic acid with chemical formula of C6H7KO2 and IUPAC-ID name of

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potassium (2,4-hexa-2,4-dienoate) that specified by name of E-202 in food industry. It is a white,

odorless and crystalline substance in the form of granule or powder with molecular mass 150.22

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g/mol and melting point of 270℃ (518 °F; 543 °K) (Erich Lück, Jager, & Raczek, 2000).

Antimicrobial effect of PS is dependent on dissociated sorbic acid and pH. The pKa of sorbate is

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4.7 at pH 4.4, where 70% of this compound is unionized, while at pH equivalent to 7 only 0.6%

of it is unionized. Thus, its activity mostly occurs at pH below 7.4. This compound dissolves

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hardly in ethanol and acetone and easily dissolves in water (58.5 g/100 mL at 100 ℃),

chloroform and corn oil, while it is insoluble in benzene. Besides, its solubility is dependent to
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water temperature. As the water temperature rises, their solubility enhances but in the presence

of high amount of ethanol it decreases. Parameters including temperature, pH, food combination,
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water activity, various metal, and other additives in food may influence PS stableness (Carine
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Ferrand, Marc, Fritsch, & De Blanquat, 2000; Yarramraju, et al., 2007).

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3. Analysis methods of potassium sorbate in food

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Analysis of various preservatives in foodstuffs is an important issue for the regulatory authorities
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and food industry. Establishment of quantitative determination methods are required for

assessment of consumer intake levels of specific presevatives such as PS in the acidic or anionic

form in foodstuff (El-Ziney, 2009; Gören, et al., 2015). The most commonly used analytical

methods for the quality assurance of sorbates in food are spectrophotometery, gas

chromatography–mass spectrometry (GC-MS), liquid chromatography–mass spectrometry (LC-

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MS), capillary electrophoresis, and high-performance liquid chromatography (HPLC) equipped

with an ultraviolet detector or a UV-diode array detector (DAD). Among them, GC-MS can be

reliable method for measurement of PS but Pylypiw et al. and Esfandiari et al introduced HPLC

as a more accurate and fastest method for determination of sorbate in foodstuff (Esfandiari, et al.,

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2013; Pylypiw & Grether, 2000).

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4. Potassium sorbate as a food preservative

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Food preservatives is composed of antimicrobials, antibrowning and antioxidants agents.

Antimicrobial preservative are a class of food additive which used to increase the shelf-life of

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food products via protection of them against deterioration caused by pathogenic microbial
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agents. Sorbate salt and sorbic acid as simple practical preservative have been consumed in food
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industry all over the world. The annual global production of PS is 38,000 tons. It is found in the

ingredients list of many dried fruit products and also a high percentage of this amount is used in
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food products (Kielhorn, Mangelsdorf, & Ziegler-Skylakakis, 2008). It is commonly used to

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increase the shelf life of commercial goods without affecting the organoleptic properties of the

food. PS prevents growth of yeasts, mold, and bacteria in food products and can be used as
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substitute of parabens (Heydaryinia, Veissi, & Sadadi, 2011; Stanojevic, Comic, Stefanovic, &

Solujic-Sukdolak, 2009). Accordingly, the use of sorbic acid and its salts is not limited in foods
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with high acidity and adequate acidity for inhibition of the microorganisms growth in these
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products is needed. The use of PS is not recommended in corrupted and alkaline foodstuffs.

However, in food products such cakes, pickles, sweets, cheeses, soft and alcoholic drinks,

sauces, salad dressing, dairy, margarine, deserted fruit juice, canned tomato paste, marine

products, vegetable products, wine, eggs syrups, and bakery (Amirpour, et al., 2015; Caleja, et

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al., 2016; Mamur, et al., 2010). The joint FAO/WHO expert committee on food additives

(JECFA) as the famous world health organization and food and agriculture organization of the

United Nations recommended the authorized PS limit of 0-25 mg/kg. In Iran and USA, this

amount is 0.01% and 0.03%, respectively but in Europe, this value is 3 mg/kg by the European

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Food Safety Authority (EFSA). But the maximum authorized amounts of PS in table olives are

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1000 mg/kg (Rahman, 2007; Stanojevic, et al., 2009). For example, the sorbate use with

concentrations of 0.025-0.1% with the acceptable human daily intake is 12.5 mg/kg according to

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JEFCA (Organization, 2012). The maximum concentration of PS in the pharmaceutical industry

and cosmetics products is 5% (Han, 2003). Finally it should be stated that PS and sorbic acid are

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authorized food additives in Japan, Australia, Canada, Europe, New Zealand and several other
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countries (Magnuson, et al., 2013).
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4.1. Potassium sorbate reaction in food

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It is known that the stability of PS in foodstuffs is influenced by so many factors such as pH ratio
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and water activity, temperature, food combination, metal ions, packaging and presence of other

food additives. The sorbate is relatively unstable and degrades in aqueous model of food systems
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and 35% of it losses after three months of storage at 30 °C and in foods with intermediate

moisture, less than 25 % after 40 days remains at 35 °C. The sorbate reacts with other groups in
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food products such as carboxyl group and forms conjugates with them through double bonds.
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Thus, by degradation and polymerization of the sorbate via oxidating agents at the conjugated

double bonds (CDB), the peroxides and degradated products such as carbonyl compounds

including malondialdehyde, croton-aldehyde, and fumaraldehydic acid (FA) are generated. It has

been shown that sorbate in food products can react with the secondary amines, ascorbic acid and

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ferrous salts and form different adducts at high temperatures, which in turn leads to the food

browning (C Ferrand, Marc, Fritsch, Cassand, & de Saint Blanquat, 2000; Thakur, Singh, &

Arya, 1994). But the potent reactivity of sorbate in the presence of iron salts such as gluconate,

citrate, and ferric might leads to the formation of toxic compounds (Kitano, Fukukawa, Ohtsuji,

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Masuda, & Yamaguchi, 2002). Sorbic acid may also react with nitrite and produce mutagenic

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1,4-dinitro-2 methylpyrrole compound that is stable at a wide range of pH (Pérez-Prior, et al.,

2009; Pérez-Prior, et al., 2008).

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4.2. Antibacterial and antifungal properties of potassium sorbate

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It has been well documented that sorbates control mold and bacteria growth and inhibit the
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mycotoxins produced by various mold strains (Stopforth, Sofos, & Busta, 2005). The mechanism

of inhibition or decreased constitutional growth by sorbates is dependent on the microbial

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species, types, strains, structural properties, and various environmental factors. The antimicrobial
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activities of sorbic acid and PS have been studied broadly. The sorbates have a high effect on
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growth rate of bacterial such as Escherichia coli, Staphylococcus aureus, Clostridium

sporogenes, Klebsiella pneumonia, Pseudomonas aeruginosa, Pseudomonas fluorescens,

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Pseudomonas cepacia Candida albicans, Saccharomyces cerevisiae, Aspergillus niger,

Penicillium notatum. But some reports showed that sorbates have a low effect on growth rate of
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bacterial such as Bacillus cereus, Campylobacter jejuni, and Enterobacter aerogenes via an
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extension in the microbial lag phase. Some microbial strains are resistant to sorbates or even

metabolize this substance under certain circumstances like lactic acid bacterias (Stanojevic, et

al., 2009). Accordingly, sorbate shows a higher inhibitory effect against molds and yeasts

compared to bacteria. Many studies have recently reported the antimicrobial mechanism of PS.

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However, the exact mechanisms of antimicrobial effects of sorbates on growth, proliferation, and

spore-forming microorganisms have not been well defined yet (Nair, Upadhyaya, Amalaradjou,

& Venkitanarayanan, 2017). The antimicrobial action of PS is possibly due to its intact

molecular chain. Probably, sorbates inhibit microbial growth by alterations in the morphology

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and function of cell membranes (Fig. 2) and inhibition of transport functions and metabolic

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activity (Alsudani, 2017; Stopforth, et al., 2005). Sorbates may influence substrate and electron

transport mechanisms. It seems that sorbic acid binding to cell membrane causes functional

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impairment of active membrane transport proteins in vitro (Alnoman, Udompijitkul, Paredes-

Sabja, & Sarker, 2015; Stopforth, et al., 2005).

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Sorbates are known as an activity inhibitor of various enzymes in vitro, especially sulphydryl-
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containing enzymes (SE). It is notable that this additive can stop the specific enzyme activity

upon addition to the production process for the first time (Barzegar, Azizi, Barzegar, & Hamidi-
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Esfahani, 2014; Stopforth, et al., 2005). Also PS may interference with cell membrane and
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electron transport mechanisms, possibly through the binding of sorbate into the cell membrane,
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where it may cause deficiency in active transport of various proteins in bacteria. Another

mechanism suggested for the cell inhibitory function of sorbate in cell growth is the excessive
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consumption of cellular energy that occurs as a consequence of the cell stimulating and cell

signaling and stress responses (Bracey, Holyoak, & Coote, 1998). Also it has been reported that
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microbial death upon increasing of sorbate concentration is related to the generation of holes on
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cellular membrane surface (Freese & Levin, 1978).

The lowest concentration of an antimicrobial agent at which there was no visible growth of the

microbe is called the minimum inhibitory concentration (MIC) (Stanojevic, et al., 2009). MIC

values of PS compared to other preservatives such as sodium benzoate and sodium nitrite has

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been presented in table 1. As it is obvious in table 1 the effectiveness of food preservatives

against various microorganisms depends on their concentration, type, pH value and the species

of microorganism on which they act (Kumar, Jayanthi, Saranraj, & Karunya, 2015; Luciana

Gerez, Yanina Bustos, & Font de Valdez, 2017; Stanojevic, et al., 2009).

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5. Metabolism and pharmacokinetics studies of sorbate

The results of metabolic studies indicated that PS is completely absorbed after oral

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administration and subsequently distributed in the body. It can be metabolized and oxidized into

carbon dioxide (CO2) and H2O like hexanoic acid in human body. 80-86% of it exhaled through

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lungs as CO2 and 2-10% of PS excreted via urine as urea and in lower concentrations as muconic
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and sorbic acid. Excretion via the lung is completed after 10 hours of application. For this
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reason, the use of this component in food has been considered as GRAS (Taghavi, et al., 2013).

The living organisms may be exposed to synthetic chemicals in several ways, which has been
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shown in Fig. 3. The metabolism of this substance in the human body can finally decompose in
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active compounds that reacts with DNA and leads to its fregmentetion and damages (Fig.4)

(Dolatabadi & Kashanian, 2010; Mpountoukas, Vantarakis, Sivridis, & Lialiaris, 2008). The
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main ways of chemicals exposure includes inhalation, skin, and oral routes (Deshpande, 2002).

As it is shown in Fig. 5, PS can form covalent binding with Lys-190 of human serum albumin
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(HSA) residues and can result in conformational changes of the protein, oxidative stress, amyloid
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fibril formation of albumin and interferences with human diseases such as diabetic and obesity

(Deshpande, 2002; Sattarahmady, et al., 2008; Taghavi, et al., 2016). It can also act as a starter

for the formation of subsequent products in organisms like advanced glycation end products

(AGEs), reactive oxygen species (ROS), and Amadori products such as ketamine that leads to

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other important changes in the presence and absence of glucose (Radoi, Lixandru, Mohora, &

Virgolici, 2012; Taghavi, et al., 2016). Although the half-life of PS shows that the human body

can metabolize it but in some cases (e.g., liver and kidney abnormalities) it enters to body

continuously in various modes without any metabolization (Deshpande, 2002). According to

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molecular docking data of PS interaction with HSA, there is a physical bind with a non-covalent

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nature in the PS interaction with domains IA and IB of this protein. Also, LIGPLOT software

studies confirmed that there is a non-covalent binding between four amino acids (Pro, Arg, His,

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and Arg) of HSA′s IA and IB domains with PS (Fig. 6). In this regard, Taghavi et al investigated

the effecte of PS as an AGE activator on HSA in the presence and absence of glucose by

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fluorescence and circular dichroism spectroscopies (Fig. 7) and concluded that in the presence or
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absence of glucose, PS leads in glycation and fibrillation of HSA and could exacerbate

complication of diabetes (Taghavi, et al., 2013).

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PS is absorbed via a diffusion process in the stomach and it can be dissociated into its
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constituents (potassium and sorbate) and absorbed through small intestine in the form of sorbic
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acid (Walker, 1990). Regarding the tissue distribution, 85% of the sorbic acid was metabolized

to carbon dioxide, 3% of it was remained in internal organs, 3% of it was found in the skeletal
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muscles, approximately 2% was excreted in the urine as urea and 0.4% in the feces, and 6.6%

was found in the other parts of the body. The further study in mice showed that 81% of PS was
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released as carbon dioxide in lung tissue and 4% was found in the urine as sorbic acid depending
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on administered dose. The fecal excretion was 0.6 to 1% in mice feeded with PS. Raharjo 1994

and sofos 1989 reported that sorbic acid, as the aliphatic carboxylic acid, may be metabolised by

organisms similar to fatty acids. The metabolic breakdown of sorbates includes activation by

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coenzyme A, hydration by crotonase to a β-hydroxy acid, dehydration to a β-keto acid and

cleavage by β-keto-thiolase (Raharjo, 1994; Sofos, 1989).

6. Toxicity and side effects of PS

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Toxicological and safety assessments require novel strategies for evaluation of preservatives risk.

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Although several studies showed toxicity of various preservatives such as PS in animal models

but the exact mechanism of PS toxicity on various cells and animals is not well understood.

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(Stanojevic, et al., 2009; Türkoğlu, 2007). It should be noted that even though sorbate is used

legally in the food industry, it might result in harmful side effects such allergy, urticaria, and

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asthma when the its intake be higher than the authorized limits (Taghavi, et al., 2013; Zamani
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Mazdeh, et al., 2014). Its long-term use can cause complications like shortness of breath,
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headaches, chest pain, swelling of the airways or bronchial spasm, mucosal irritation, pulmonary

edema, and stimulation of the respiratory tract as a result of the inhalation of this chemical and
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occupational pollution (Lebe, et al., 2004; Mamur, et al., 2010). However, nonirritating effects
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have been observed in rabbit's eye exposed to sorbate with dose of higher than 10% (Currance,

Clements, & Bronstein, 2006). In addition, no cytostatic activity at concentrations of 2.0, 0.2,
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and 0.02 mM of PS has been reported (Mpountoukas, et al., 2008). PS containing materials such

as toothpaste and dairy products led to the irritation and long-term sensitivity of oral slot and
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skin irritations after using by the consumer (Le Coz & Abensour, 2005). Eating high doses
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causes chromosomal aberrations in human blood lymphocytes, eye irritation, aged contact

dermatitis (Fisher, 1980; Furia, 1972). It has been shown that sorbate induces genotoxic or

mutagenic effects in the human peripheral blood lymphocytes in vitro. Also, sorbate affects lipid

peroxidation (LP) and damages the rat hepatocyte cell and its membrane (Mamur, et al., 2010).

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Also it has been shown that formation of mutagenic products was due to reaction between sorbic

acid and nitrite in food products (Walker, 1990).

The lethal oral dose (LD) of sorbic acid in rats is 50 mg/kg. The LD50 of the PS has also been

determined between 4,200 and 6,170 mg/kg-BW. Also the LD50 for human was 500 mg/kg that

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reported by JECFA (1974) (Joint & Additives, 1974).

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In a study by Ishidate et al., sorbic acid with a concentration of 10 mg was evaluated for its

mutagenicity via Ames test with the Salmonella tester strains TA1537, TA1535, TA98, and

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TA100 using the incubation method both in the absence and the presence of metabolic activation

system of rat liver S9 fraction (Ishidate, et al., 1984). Also Hasegawa et al showed that sorbic

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acid with concentrations of 350 mg/kg in a Chinese hamster V79 cell line induced chromosomal
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damage, sister chromatid exchanges (SCEs), and gene mutations at the hypoxanthine-guanine

phosphoribosyltransferase after 24 h (Hasegawa, Nishi, Ohkawa, & Inui, 1984). Potential

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genotoxicity of sorbic acid in concentrations of 120 mg/mL on Syrian hamster embryo fibroblast
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using in vitro micronucleus assay after 18 h of teatment was demonstrated by Schiffmann et al

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(Schiffmann & Schlatter, 1992). Mamur et al. investigated the possible genotoxic of sorbate

using the chromosomal breaks, sister chromatid exchanges and micronucleus assays and
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evaluated the induction of DNA damage by alkaline comet assay in human lymphocytes treated

with concentrations of 125 and 250 mg/mL for 24 and 48 h (Mamur, et al., 2010). In addition,
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one of the main toxic effects of sorbate is induction of skin, eye, and respiratory irritation
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(Mamur, et al., 2010). It has mutagenic and genotoxic effects on human blood cells and is toxic

to human peripheral blood lymphocytes DNA (Mamur, et al., 2010). It is frequently used with

acid ascorbic and iron salts due to its more inhibition efficiency, however, these two materials

tend to form mutagenic compounds that cause DNA damage (Kitano, et al., 2002). Several

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studies have shown that sorbate can alter liver function and lead in allergy (Brahmachari &

Pahan, 2007). Cytotoxic, mutagenic, and clastogenic effects of sorbic acid were investigated on

human lymphocytes in vitro and it has been concluded that it may cause cancer (Soares, et al.,

2015; Türkoğlu, 2007). Raposa et al. showed that expressions of NFκB, GADD45α, and MAPK8

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genes in cell inflammation, proliferation, and apoptosis affect the liver of mice fed with sorbate

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additive (Raposa, et al., 2016). However, it seems that cell cycle process changes at a high

concentration was based on the expression of GADD45α gene (Sheikh, Hollander, & Fornace,

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2000). DNA strand damage and carcinogenic upon treatment with sorbate has been confirmed

through addition of nucleophile 4-(p-nitrobenzyl)pyridine alkylating agent (Pérez-Prior, Manso,

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García-Santos, Calle, & Casado, 2005). It has been reported that sorbic acid at high temperatures
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(60-70 ºC) and concentrations reacts with nitrites and forms mutagenic materials (Namiki,

Udaka, Osawa, Tsuji, & Kada, 1980). Eating too much sorbate preservative over a long period of
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time could cause symptoms such as vomiting, nausea, diarrhea, and stomach discomfort
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(Godbole, 2013; Zengin, Yüzbaşıoğlu, Ünal, Yılmaz, & Aksoy, 2011). Also pharyngeal lesions,
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cell inflammation, epithelial glandular formation, vascular hyperplasia, and edematous exchange

has been observed even at low dose of sorbate at in vivo studies (Bryant, 1998; Sandberg, 1991).
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Munzner et al. showed weak clastogenic activity of PS at chinese hamster ovary cells through

increase of chromosome aberrations and micronuclei at doses of 200 mg/kg-BW but it did not
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affect SCEs (Münzner, Guigas, & Renner, 1990). Toxicological effects of PS both at in vitro and
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in vivo conditions are summarized in Table 1. Finally, it should be noted that chromatid

aberration, DNA strand breaks, and sister chromatid exchange can trigger the development of

cancer in human (Bryant, 1998; Sandberg, 1991).

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7. Conclusions

PS possesses high antimicrobial properties and is widely used in food, cosmetics, and

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pharmaceutical industries. PS can be metabolized and oxidized into carbon dioxide and water in

the human digestive system. However, it may directly enter into biological process through

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consumption of food products and various drugs and results in nutritional deficiency and

numerous diseases and the side effects of sorbate have been approved on human health at high

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doses. Many researchers have previously shown successful incorporation of synthetic additives

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with various objectives in foods. However, further studies and survey about application of this
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additive in the food industry are required. Furthermore, various research may be necessary and

useful for changing the attitude of industries toward the use of PS as a harmless preservative,
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which may lead to its applications more cautiously. This overview shows that PS can have side

effects on human health through activation of inflammatory routes, exacerbation of diabetes and
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triggering of the gradual development of cancers. Therefore, we emphasize that PS additive

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intake in the human dietary should be reduced and only the legal limit of additives ought to be

used in the manufacturing process.

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Conflict of interests
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The authors declare that they have no conflict of interests.

Acknowledgment

The authors gratefully acknowledge the financial support of this study by the Tabriz University

of Medical Sciences, which was a part of M.Sc thesis No: 117, Tabriz, Iran.

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Table 1. Minimum inhibitory concentration (MIC) values of Potassium sorbate compared to

sodium benzoate and sodium nitrite. Reused with permission from ref (Stanojevic, et al., 2009).

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Microorganism species MIC (mg/ml)

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Potassium sorbate Sodium benzoate Sodium nitrite

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Escherichia coli 5 5 2

Bacillus mucoides 10 10 2

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Bacillus subtilis 10 10 1
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Staphylococcus aureus 10 10 1

Pseudomonas aeruginosa 10 5 0.5

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Aspergillus flavus 50 50 50
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Candida albicans 50 2.5 50

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Penicillium italicum 15 20 50

Fusarium oxysporum 7.25 20 3.25

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Trichoderma harzianum 30 30 50
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Table 2. Toxicological effects of potassium sorbate both at in vitro and in vivo conditions.

Toxicity type Target cells Concentration of PS Assessment metoud Ref

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Mutagenicity Salmonella 10 mg/kg Ames test (Ishidate, et
tester strains
al., 1984)

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Gene mutations at the Chinese 350 mg/kg sister chromatid (Hasegawa,
hypoxanthine-guanine exchanges
hamster V79

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phosphoribosyltransferase et al., 1984)

Potential genotoxicity Syrian 120 mg/kg Micronucleus assay (Schiffmann

hamster

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& Schlatter,
embryo
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1992)
fibroblast
Cyto/genotoxic and human 250 mg/kg sister chromatid (Mamur, et
DNA damage lymphocytes exchanges and
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micronucleus assays al., 2010)

Expressions of NFκB,
GADD45α, and MAPK8 liver of mice 500mg/kg Gene expression (Raposa, et
genes and cancers
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analysis al., 2016)

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Mutagenicity and DNA- Salmonella 150 mg/kg Rec-assay and ames (Kitano, et
damaging activity. strains of
TA98 and test al., 2002)
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Figure legends

Fig. 1. Chemical structure of potassium sorbate

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Fig. 2. Potential antibacterial mechanism of potassium sorbate against membrane surface of E.

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coli O157:H7

Fig. 3. Absorption, distribution and excretion of potassium sorbate in human body

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Fig. 4. Metabolism process of potassium sorbate in body

Fig. 5. Biological and toxicological effects of potassium sorbate on HSA.

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Fig. 6. Docking results of HSA complex with PS. PS–HSA interaction site is shown by an arrow.
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Fig. 7. (a–e) shows the fluorescence spectra of control HSA (HSA35D) and modified HSA (HSA

+ Glc, HSA + PS, and HSA + Glc + PS after incubation at 37 ºC for 35 days) with AGEs at
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various excitation wavelengths (322 nm, 335 nm, 365 nm, 375 nm and 380 nm). Republished
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with permission from (Taghavi, et al., 2013).

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• Pharmacokinetic and toxicity effects of potassium sorbate have been reviewed.

• Potassium sorbate showed cytotoxic and genotoxic effects.

• Potassium sorbate induced chromosome aberrations and DNA breakage.

• Sorbates are known as an activity inhibitor of various enzymes in vitro.

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