Re: 철분 과잉 --＞ 펜톤반응 --＞ ferroptosis(세포 사멸).. 탐구..

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Open AccessReview

Current Use of Fenton Reaction in Drugs and Food

by 

Chizumi Abe

,

Taiki Miyazawa

 and

Teruo Miyazawa

 *

New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai 980-8579, Japan

*

Author to whom correspondence should be addressed.

Molecules 2022, 27(17), 5451; https://doi.org/10.3390/molecules27175451

Submission received: 31 July 2022 / Revised: 22 August 2022 / Accepted: 23 August 2022 / Published: 25 August 2022

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Abstract

Iron is the most abundant mineral in the human body and plays essential roles in sustaining life, such as the transport of oxygen to systemic organs. The Fenton reaction is the reaction between iron and hydrogen peroxide, generating hydroxyl radical, which is highly reactive and highly toxic to living cells. “Ferroptosis”, a programmed cell death in which the Fenton reaction is closely involved, has recently received much attention. Furthermore, various applications of the Fenton reaction have been reported in the medical and nutritional fields, such as cancer treatment or sterilization. Here, this review summarizes the recent growing interest in the usefulness of iron and its biological relevance through basic and practical information of the Fenton reaction and recent reports.

철은

인체에서 가장 풍부한 미네랄이며,

산소를 조직 기관으로 운반하는 등 생명 유지에 필수적인 역할을 합니다.

펜톤 반응은

철과 과산화수소가 반응하여

생체 내 반응성이 높고 독성이 강한 하이드록실 라디칼을 생성하는 반응입니다.

최근

펜톤 반응이 밀접하게 관여하는 프로그램화된 세포 사멸인

'페로토시스'가 많은 관심을 받고 있습니다.

또한,

펜톤 반응의 다양한 응용 사례가 암 치료나 살균과 같은

의료 및 영양 분야에서 보고되고 있습니다.

이 글에서는

펜톤 반응의 기초적이고 실용적인 정보와 최근 보고서를 통해

철의 유용성과 생물학적 관련성에 대한 최근의 증가하는 관심을 요약합니다.

Keywords: 

antioxidants; cancer; Fenton reaction; hydrogen peroxide; hygiene; iron; nanomedicine; oxidative stress; polyphenol; vitamin C

1. Introduction

It has only been around 100 years since people started research on food in terms of “modern nutritional science” [1]. In the latter part of the 1800s, Lavoisier investigated chemical oxidation in living things, which is thought to be the beginning of nutritional science. In the early 1900s, individual food components began to be found. For example, vitamin B1 (oryzanin) was found in trials to overcome the deficiencies of military patients [2]. Vitamin E was isolated from wheat germ oil, which was found to be involved in rat reproduction [3]. In contrast, the discovery of minerals dates back to 6000 B.C, but it took centuries to recognize their roles in biological systems. Among the various minerals, iron is one of the well-known and -utilized minerals from ancient times and was estimated to be present in the blood in the 1700s [4]. Iron is the most abundant transition metal on Earth’s surface, with 3–4 g of iron in the body of a healthy adult human [5,6]. Since iron is the most abundant transition metal in the human body, its contribution toward various biological activities has long been the focus of growing attention [7]. For example, anemia is one of the major manifestations of iron deficiency. In 1925, Fontès and Thivolle found that iron-deficient horses had lower serum iron concentrations [8]. In the human body, most extracellular iron is bound to iron-binding proteins (such as transferrin and lactoferrin) [9]. Heme proteins in red blood cells play an important role in transporting oxygen to organs [10].

On the other hand, iron is involved not only in the delivery of oxygen in our body but also in DNA synthesis and/or repair [11], indicating this mineral is essential for the survival of living things. Iron also works as a cofactor to facilitate various enzymes, such as catalase and cytochromes. The roles of iron in the body are particularly involved in redox reactions due to its preferable affinity to oxygen. In the 1890s, Henry John Horstman Fenton found the redox reaction between iron (II) and hydrogen peroxide (H2O2) to produce hydroxyl radical (OH•), called the Fenton reaction [12]. This reaction potentially occurs in the human body and is thought to regulate complicated systems, which is related to homeostasis. The products of the Fenton reaction OH• is highly reactive particles that induce oxidative damage to cells, but this is also an aspect that can be a therapeutic strategy for cancer patients. Several medicines (e.g., doxorubicin (DOX) [13], β-lapachone [14], and cisplatin [15]) include mechanisms of reaction that have applied the Fenton reaction to generate the poison, OH•, to cancer cells. Additionally, numerous food components daily consumed have beneficial effects in the human body, such as on chronic diseases and on immune systems [16,17,18]. The antioxidant reaction is one of the major properties of such food components (e.g., polyphenols and vitamins). Considering reactive oxygen species (ROS) generated by vitamin C [19] and chelating metal iron by flavonoids [20], iron potentially affects the bioactivities of absorbed and metabolized food components in the body. Furthermore, there is growing interest in programed death “ferroptosis” related to the Fenton reaction [21]. Against these backgrounds, this review summarizes the recent growing interest in the usefulness of iron and its biological relevance through basic and practical information of the Fenton reaction and recent reports.

1. 서론

사람들이 “현대 영양학”의 관점에서 음식에 대한 연구를 시작한 지 100년밖에 되지 않았습니다 [1]. 1800년대 후반에 라부아지에(Lavoisier)는 생명체의 화학 산화에 대해 연구했는데, 이것이 영양학의 시작이라고 여겨집니다. 1900년대 초반에 개별 식품 성분이 발견되기 시작했습니다.

예를 들어, 비타민 B1(오리잔틴)은 군인 환자의 결핍을 극복하기 위한 실험에서 발견되었습니다 [2]. 비타민 E는 밀 배아유에서 분리되었으며, 쥐의 번식에 관여하는 것으로 밝혀졌습니다 [3]. 이와는 대조적으로, 미네랄의 발견은 기원전 6000년으로 거슬러 올라가지만, 생물학적 시스템에서 그 역할을 인식하는 데는 수 세기가 걸렸습니다. 다양한 광물 중에서 철은 고대부터 잘 알려져 있고 많이 이용된 광물 중 하나이며, 1700년대에는 혈액에 존재하는 것으로 추정되었습니다 [4].

철은

지구 표면에서 가장 풍부한 전이 금속으로,

건강한 성인 인체의 체내에는 3-4g의 철이 존재합니다 [5,6].

철은

인체에서 가장 풍부한 전이 금속이기 때문에,

다양한 생물학적 활동에 대한 철의 기여도는 오랫동안 주목을 받아 왔습니다 [7].

예를 들어,

빈혈은 철분 결핍의 주요 증상 중 하나입니다.

1925년, Fontès와 Thivolle은 철분이 결핍된 말의 혈청 철분 농도가 낮다는 것을 발견했습니다 [8]. 인체에서, 대부분의 세포 외 철분은 철 결합 단백질(예: 트랜스페린과 락토페린)에 결합되어 있습니다 [9].

적혈구의 헴 단백질은

산소를 장기로 운반하는 데

중요한 역할을 합니다 [10].

한편,

철분은 우리 몸에서 산소를 운반하는 것뿐만 아니라

DNA 합성 및/또는 복구에도 관여합니다 [11],

이 미네랄이 생명체의 생존에 필수적임을 나타냅니다.

철분은 또한

카탈라제와 시토크롬과 같은 다양한 효소를 촉진하는

보조 인자 역할을 합니다.

철의 역할은

산소와 친화력이 좋아

산화 환원 반응에 특히 관여합니다.

1890년대,

헨리 존 호스트만 펜턴(Henry John Horstman Fenton)은

철(II)과 과산화수소(H2O2) 사이의 산화 환원 반응으로

하이드록실 라디칼(OH•)을 생성하는 펜턴 반응[12]을 발견했습니다.

이 반응은

잠재적으로 인체에서 발생하며,

항상성과 관련된 복잡한 시스템을 조절하는 것으로 여겨집니다.

펜톤 반응의 산물인 OH•는

세포에 산화적 손상을 유발하는 반응성이 매우 높은 입자이지만,

암 환자의 치료 전략이 될 수 있는 측면이기도 합니다.

여러 가지 약품(예: 독소루비신(DOX) [13], β-라파콘 [14], 시스플라틴 [15])에는

펜톤 반응을 적용하여

독성 물질인 OH•를 생성하는 반응 메커니즘이 포함되어 있습니다.

또한,

매일 섭취하는 수많은 식품 성분은

만성 질환과 면역 체계에 유익한 영향을 미칩니다 [16,17,18].

항산화 반응은

이러한 식품 성분(예: 폴리페놀과 비타민)의 주요 특성 중 하나입니다.

비타민 C에 의해 생성되는 활성산소(ROS) [19]와

플라보노이드에 의한 금속 철의 킬레이트화 [20]를 고려할 때,

철은 흡수되고 대사된 식품 성분의 생체 활성에 잠재적으로 영향을 미칠 수 있습니다.

https://www.mdpi.com/1420-3049/19/11/18296#

https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.972198/full

- 한약 플라보노이드가 구리 킬레이션 효과가 있다는 논문...

또한,

펜톤 반응과 관련된 프로그램된 죽음 “페로톡시시스”에 대한 관심이 증가하고 있습니다 [21].

이러한 배경에서, 이 리뷰는 펜톤 반응에 대한 기초적이고 실용적인 정보와 최근 보고서를 통해 철의 유용성과 생물학적 관련성에 대한 최근의 증가하는 관심을 요약합니다.

2. Fenton Reaction

The Fenton reaction is the reaction of iron (II) with H2O2, reported by Henry John Horstman Fenton in 1894 [12]. In 1876, his student found that a mixture of H2O2, tartaric acid, ferrous salt and water turned a violet color. This is known as the Fenton reaction (Reaction (1)):

2. 펜톤 반응

펜톤 반응은 1894년 헨리 존 호스트만 펜톤(Henry John Horstman Fenton)이 보고한 철(II)과 H2O2의 반응입니다 [12]. 1876년, 그의 학생은 H2O2, 타르타르산, 철염, 물의 혼합물이 보라색으로 변한다는 것을 발견했습니다. 이를 펜톤 반응이라고 합니다 (반응 (1)):

Fe2+ + H2O2 → Fe3+ + OH− + OH•

(1)

While Fenton speculated the mechanism of oxidation by H2O2 and iron (II), some researchers doubted the formation of OH• in one-electron reduction by iron (II). In 1931, Haber and Wilstatter mentioned the hydroxy radical in radical chain mechanisms (Reaction (2) and (3)) [22]. They described that chain reactions are initiated by enzymes, specifically catalase:

펜톤은 H2O2와 철(II)에 의한 산화 메커니즘을 추측했지만, 일부 연구자들은 철(II)에 의한 일전자 환원에서 OH•의 형성이 의심스러웠습니다. 1931년, 하버와 윌스타터는 라디칼 사슬 메커니즘(반응 (2)와 (3))에서 하이드록시 라디칼을 언급했습니다 [22]. 그들은 사슬 반응이 효소, 특히 카탈라제에 의해 시작된다고 설명했습니다.

OH + H2O2 → H2O + O2H

(2)

O2H + H2O2 → O2 + H2O + OH

(3)

Thereafter, Harber and Weiss explained the decomposition of H2O2 by iron (II) using Reaction (4) to (6), where the Fenton reaction initiates and Reaction (6) terminates the chain reactions [23]:

그 후, 하버와 와이즈는 반응식 (4)에서 (6)을 사용하여 철(II)에 의한 H2O2의 분해를 설명했는데, 여기서 펜톤 반응이 시작되고 반응식 (6)이 연쇄 반응을 종결합니다 [23]:

OH• + H2O2 → H2O + O2•− + H+

(4)

O2•− + H+ + H2O2 → O2 + H2O + OH•

(5)

Fe2+ + HO + H+ → Fe3+ + H2O

(6)

In 1937, Weiss explained the reaction mechanism of catalase: an anion H2O2 reduces iron (III) to iron (II), and then iron (II) reduces H2O2 to OH• and water, followed by chain reaction (5, 6), which is collectively referred to as the Haber–Weiss reaction. The mechanism of the Fenton reaction has studied and discussed, among which detailed equilibrium principles have been well summarized by Stanbury [24]. The Fenton reaction is affected by the environmental pH and concentration of iron. The major ROS generated from the Fenton reaction are oxoiron (IV) species at pH > 3, and OH• at more acidic conditions [25,26,27]. Two mechanisms, the “radical mechanism” and the “complex mechanism”, contribute to the iron-catalyzed disproportionation of H2O2 and the Fenton reaction. The products obtained from these reactions are different. In the “radical mechanism”, Fe2+ and Fe3+ react with H2O2 to produce OH• and superoxide, respectively. In the “complex mechanism”, Fe2+ and Fe3+ react with H2O2 to produce FeO2+ and FeO3 +, respectively. In 2013, more than 100 years after the Fenton reaction was proposed, successful detection of Fe(IV) was reported [28]. Additionally, it has been suggested that fellyl ion controls iron cycling by the Fenton reaction in a cloud as well as Fe2+ and Fe3+ [29]. Such reports indicate how great the impact and complexity of this reaction is. The use of other transition metals such as copper leads to a reaction similar to the Fenton reaction, called the Fenton-like reaction. Although the Fenton reaction initially began to be used for analytical purposes, chelation or sequestration of transition metals involving Fenton and Fenton-like reactions have been found to play important roles in the internal and external environments of living things.

1937년, 와이즈는 카탈라제의 반응 메커니즘을 설명했습니다:

음이온 H2O2가 철(III)을 철(II)로 환원시킨 다음,

철(II)이 H2O2를 OH•와 물로 환원시킨 후,

연쇄 반응(5, 6)이 일어납니다.

이를 통틀어 하버-와이즈 반응이라고 합니다.

펜톤 반응의 메커니즘은 연구되고 논의되어 왔으며, 그 중에서도 상세한 평형 원리가 Stanbury에 의해 잘 요약되어 있습니다 [24].

펜톤 반응은

환경의 pH와 철의 농도에 영향을 받습니다.

펜톤 반응에서 생성되는 주요 ROS는

pH가 3 이상일 때 옥소철(IV) 종이고,

산성 조건에서는 OH•입니다 [25,26,27]. “

'라디칼 메커니즘”과 “복합적 메커니즘”이라는

두 가지 메커니즘이

H2O2의 철 촉매 불균형 분해와 펜톤 반응에 기여합니다.

 “radical mechanism” and the “complex mechanism”

이러한 반응에서 얻어지는 산물은 서로 다릅니다.

“라다컬 메커니즘"에서는

Fe2+와 Fe3+가 H2O2와 반응하여

각각 OH•와 슈퍼옥사이드를 생성합니다.

‘복합 메커니즘’에서는

Fe2+와 Fe3+가 H2O2와 반응하여

각각 FeO2+와 FeO3 +를 생성합니다.

펜톤 반응이 제안된 지 100년이 지난 2013년에 Fe(IV)의 검출에 성공했다는 보고가 있었습니다 [28].

또한, 펠리실 이온은 구름 속의 펜톤 반응과 Fe2+ 및 Fe3+에 의한 철 순환을 제어한다고 제안되었습니다 [29]. 이러한 보고서는 이 반응이 얼마나 큰 영향을 미치고 복잡한지를 보여줍니다.

구리와 같은 다른 전이 금속을 사용하면

펜톤 반응과 유사한 반응이 일어나는데,

이를 펜톤 유사 반응이라고 합니다.

펜톤 반응은 처음에는 분석 목적으로 사용되기 시작했지만,

펜톤과 펜톤 유사 반응을 포함하는

전이 금속의 킬레이트화 또는 격리는

생물체의 내부 및 외부 환경에서 중요한 역할을 하는 것으로 밝혀졌습니다.

3. Fenton Reaction in Body

3.1. Iron as a Nutrient

Nutrients are essential for living things, among which proteins, fats, and carbohydrates are three major nutrients. In the context of the human diet, minerals are elements, except H, C, N, and O (the main components of three major nutrients: organic compounds), that maintain or regulate biological systems, and account for approximately 4% of the human body. Of these, 16 types of elements (Na, N, P, K, S, Ca, Mg, iodine, Se, Cr, Co, Fe, Mn, Zn, Cu, and Mo) are thought to play particularly important roles. They are classified into two groups based on the required amount (more than 100 mg/day: Na, N, P, K, S, Ca, and Mg; less than 100 mg/day: iodine, Se, Cr, Co, Fe, Mn, Zn, Cu, and Mo).

Iron is present in all human cells, with an average of 2.4 g in women and 3.8 g in men, with daily losses of 1–2 mg [30] (Figure 1). Examples of iron-rich foods include oysters, clams, mussels, beef or chicken liver, and poultry while non-heme iron is contained in beans, spinach, nuts, and seeds. One of the most important roles of iron is to transport oxygen in hemoglobin (Hb). This protein, consisting of 96% of blood cells [31], provides oxygen to the whole body from the lungs or other airway organs and supports metabolism. Hb iron binds up to four oxygen molecules in the form of Fe2+ or Fe3+ [32]. Additionally, other oxygen storage protein and enzymes bind to iron (hemoglobin, 2500 mg iron; myoglobin, 130 mg iron; enzymes, 150 mg iron) [33]. Anemia due to a general iron deficiency (Hb <13 g/dL in males, <12 g/dL in females, <11 g/dL during pregnancy) is mainly due to biological mechanisms (e.g., iron deficiency, hemolytic anemia, and anemia of inflammation) and/or erythrocyte morphology. Iron deficiency occurs when there is an insufficient supply of iron against the amount needed such as during periods of high iron requirements (e.g., infancy and pregnancy) and/or iron loss exceeds intake. Iron is absorbed via human intestinal mucosa in heme and non-heme forms, whereas heme-iron is reported to be more readily absorbed through the folate transporter [34]. Non-heme iron, Fe2+ and Fe3 +, is transported into the duodenal cytoplasm via divalent metal iron transporter-1 (DMT-1) in Fe2+ [35], where Fe3+ is previously reduced to Fe2+ by cytochrome b reductase and/or other reductants. After being transported into cells, iron either binds to ferritin for storage or is transported into the blood stream via ferroportin as Fe2 +. Iron is then oxidized by membrane-bound ferroxidase hephaestin and ceruloplasmin to be incorporated into transferrin to form the transferrin–Fe3+ complex. Hepcidin is a peptide hormone excreted from the liver that binds to ferroportin, the only iron efflux transporter in the blood, and regulates iron homeostasis by promoting internalization and degradation of the transporter [36]. Hepcidin completely occludes the iron pathway by binding ferroportin with an outward-open conformation [37]. While this section only presented limited information on iron absorption and metabolism, more detailed clinical characteristics of iron deficiency are described by Camaschella et al. and Pasricha et al. [33,38].

3. 신체 내 펜톤 반응

3.1. 영양소로서의 철분

영양소는 생명체에게 필수적인 요소이며, 그 중에서도 단백질, 지방, 탄수화물이 3대 영양소입니다.

인간의 식생활과 관련하여,

미네랄은 H, C, N, O(3대 영양소의 주성분인 유기 화합물)를 제외한

생물학적 시스템을 유지하거나 조절하는 요소이며,

인체에서 약 4%를 차지합니다.

그 중에서도

16가지 유형의 원소(Na, N, P, K, S, Ca, Mg, 요오드, Se, Cr, Co, Fe, Mn, Zn, Cu, Mo)가

특히 중요한 역할을 하는 것으로 여겨집니다.

이 원소들은 필요한 양에 따라 두 그룹으로 분류됩니다

(하루 100mg 이상: Na, N, P, K, S, Ca, Mg;

100mg/일 미만: 요오드, Se, Cr, Co, Fe, Mn, Zn, Cu, Mo).

철분은

모든 인간 세포에 존재하며,

여성의 경우 평균 2.4g, 남성의 경우 3.8g이며,

매일 1-2mg씩 손실됩니다[30] (그림 1).

철분이 풍부한 식품의 예로는

굴, 조개, 홍합, 소고기 또는 닭 간, 가금류가 있으며,

비헴철은 콩, 시금치, 견과류, 씨앗류에 함유되어 있습니다.

철의 가장 중요한 역할 중 하나는

헤모글로빈(Hb)에서 산소를 운반하는 것입니다.

이 단백질은

혈액 세포의 96%를 차지하며[31],

폐나 다른 호흡기 기관에서 온몸에 산소를 공급하고 신진대사를 돕습니다.

Hb 철은

Fe2+ 또는 Fe3+의 형태로

최대 4개의 산소 분자를 결합합니다 [32].

또한,

다른 산소 저장 단백질과 효소도 철에 결합합니다

(헤모글로빈, 2500mg 철; 미오글로빈, 130mg 철; 효소, 150mg 철) [33].

일반적인 철분 결핍으로 인한 빈혈(

남성의 경우 Hb 13g/dL 미만, 여성의 경우 12g/dL 미만, 임신 중에는 11g/dL 미만)은

주로 생물학적 메커니즘(예: 철분 결핍, 용혈성 빈혈, 염증성 빈혈) 및/또는 적혈구 형태에 기인합니다.

철분 결핍은

철분 요구량이 많은 시기(예: 유아기 및 임신)에

필요한 양에 비해 철분 공급이 부족하거나

철분 손실이 섭취량을 초과할 때 발생합니다.

철분은

헴과 비헴 형태로 사람의 장 점막을 통해 흡수되지만,

헴철은 엽산 수송체를 통해 더 쉽게 흡수되는 것으로 알려져 있습니다[34].

비헴철인 Fe2+와 Fe3+는

Fe2+ [35]의 2가 금속 철 수송체-1(DMT-1)을 통해 십이지장 세포질로 운반되는데,

이 과정에서 Fe3+는 사이토크롬 b 환원효소 및/또는 다른 환원제에 의해 Fe2+로 환원됩니다.

세포로 운반된 후,

철분은 페리틴에 결합하여 저장되거나,

페로포르틴을 통해 Fe2+의 형태로 혈류로 운반됩니다.

그런 다음,

철은 막에 결합된 페록시다아제 헤파이스틴과 세룰로플라스민에 의해 산화되어

트랜스페린에 통합되어 트랜스페린-Fe3+ 복합체를 형성합니다.

헵시딘은

간에서 배출되는 펩타이드 호르몬으로,

혈액 내 유일한 철 유출 수송체인 페로포르틴에 결합하여

수송체의 내재화와 분해를 촉진함으로써

철의 항상성을 조절합니다 [36].

헵시딘은

페로포르틴을 바깥쪽으로 열린 형태로 결합시켜

철분 경로를 완전히 차단합니다 [37].

이 섹션에서는 철분 흡수와 대사에 대한 제한적인 정보만 제공되었지만, 철분 결핍에 대한 보다 자세한 임상적 특성은 Camaschella et al.과 Pasricha et al. [33,38]에 의해 설명되어 있습니다.

Figure 1. Distribution of iron in the body and the main organs involved in the regulation of iron metabolism (modified from permission from [39] under the Creative Commons CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/ (accessed on 28 July 2022)). Values data for iron levels are obtained from Lesjac et al. [40]).

As mentioned above, iron is absorbed in the intestine as either heme or non-heme forms, but other food-derived components are also absorbed in the intestine, suggesting that interactions with them may affect iron absorption (Figure 2). For example, quercetin has been reported to inhibit intestinal iron absorption by different mechanisms, through chelation in an acute duodenal injection study and by suppressing ferroportin expression‎ in an oral administration study in rats [41]. Tea consumption also reduces the bioavailability of iron, possibly due to polyphenols such as tannins [42,43]. It has also been reported that the intake of a high-fat diet inhibits intestinal iron absorption, causing iron deficiency [44], and that the amount of absorbed iron in overweight women was two-thirds of the normal value [45]. In contrast, ascorbic acid is well known to increase iron absorption related to iron reduction and the intake of ascorbic acid attenuates the above inhibitory effect of polyphenols [46]. The major peptide hormone, hepcidin, is also affected by flavonoids; myricetin significantly suppresses the expression‎ of this hormone [47]. Higher concentrations and lower clearance of hepcidin due to chronic kidney disease suppress iron absorption, resulting in iron deficiency [48]. On the contrary, 17β-estradiol possibly promotes iron absorption by inhibiting hepcidin expression‎ through an estrogen-responsive element half-site in the promoter region of the hepcidin gene [49], indicating that increased iron might be caused by another mechanism in postmenopausal women.

위에서 언급한 바와 같이,

철분은 장에서 헴 또는 비헴 형태로 흡수되지만,

다른 식품 유래 성분도 장에서 흡수되기 때문에,

이들 성분과의 상호작용이 철분 흡수에 영향을 미칠 수 있음을 시사합니다(그림 2).

예를 들어,

케르세틴은

급성 십이지장 주사 연구에서 킬레이트화를 통해,

쥐를 대상으로 한 경구 투여 연구에서 페로포르틴 발현을 억제함으로써

다양한 메커니즘을 통해 장내 철분 흡수를 억제하는 것으로 보고되었습니다[41].

또한

차를 마시면 철분의 생체 이용률이 감소하는데,

이는 탄닌과 같은 폴리페놀 때문일 수 있습니다[42,43].

또한 고지방 식사를 하면 장에서 철분의 흡수가 억제되어 철분 결핍이 발생한다는 보고가 있습니다[44].

과체중 여성의 경우,

흡수된 철분의 양이 정상 수치의 3분의 2에 불과하다는 보고도 있습니다[45].

반면,

아스코르브산은 철분 감소와 관련된 철분 흡수를 증가시키는 것으로 잘 알려져 있으며,

아스코르브산을 섭취하면 폴리페놀의 억제 효과가 약화됩니다 [46].

주요 펩타이드 호르몬인 헵시딘도

플라보노이드의 영향을 받습니다.

미리세틴은 이 호르몬의 발현을 현저하게 억제합니다 [47].

만성 신장 질환으로 인해

헵시딘의 농도가 높아지고 제거율이 낮아지면

철분 흡수가 억제되어 철분 결핍이 발생합니다 [48].

반대로, 17β-estradiol은 헵시딘 유전자의 프로모터 영역에 있는 에스트로겐 반응성 요소 반쪽 부위를 통해 헵시딘 발현을 억제함으로써 철분 흡수를 촉진할 가능성이 있습니다 [49]. 이는 폐경 후 여성의 철분 증가가 다른 메커니즘에 의해 유발될 수 있음을 나타냅니다.

Figure 2. Absorption behavior of iron in the intestine and the interaction with molecules derived from food (modified with permission from [50] under the Creative Commons CC BY 4.0 license, https://creativecommons.org/licenses/by/4.0/ (accessed on 28 July 2022)).

3.2. Fenton Reaction under Biological Environment

Iron is transferred from binding in transferrin as Fe3+ form and transported into cells via the transferrin receptor. Most transition metals, including iron, are involved in the generation of various free radicals due to their redox features. As “second-messengers”, ROS play essential roles in cellular life cycles, such as proliferation [51] and gene expression‎ [52] (Figure 3). Observation with fluorescent reagents (e.g., dihydrorhodamine, coumarin-3-calboxylic acid, and endoplasmic reticulum (ER)-targeting OH• probe) has revealed intracellular localization of the generated OH•. Such studies have reported that ER by the Fenton reaction [53,54] regulates hypoxia-inducible gene expression‎. ER stress has been reported to regulate more than one-third of all proteins made in the cell in synthesis, folding, and structural maturation [55]. Additionally, H2O2, one type of ROS generated extracellularly, penetrates the cell membrane easily to react with intracellular iron (Fe2+ and Fe3 +), producing OH• through the Fenton and Fenton-like reaction. OH• reacts most strongly with biomolecules shorter than 1 ns [3,56], which results in the most severe damage to biological systems among ROS. It involves the induction of the oxidation of molecules. OH• produced through the Fenton reaction has been reported to induce DNA damage [57]. Iron released from Hb is also known to promote the degradation of deoxyribose, inducing lipid peroxidation [58,59]. Additionally, Fenton-type chemistry (e.g., peroxidases, free heme, and metal ions) is involved in the tyrosine nitration observed within tyrosine residues in proteins and used as a signature for peroxynitrite [60].

3.2. 생물학적 환경에서의 펜톤 반응

철은

트랜스페린 결합에서 Fe3+ 형태로 이동하여

트랜스페린 수용체를 통해

세포로 운반됩니다.

철을 포함한 대부분의 전이 금속은

산화 환원 특성으로 인해

다양한 자유 라디칼의 생성에 관여합니다.

“제2 메신저”로서,

ROS는

증식[51] 및 유전자 발현[52]과 같은 세포의 생명 주기에서 필수적인 역할을 합니다(그림 3).

형광 시약(예: 디하이드로로다민, 쿠마린-3-칼복실산, 소포체(ER) 표적 OH• 프로브)을 이용한 관찰 결과,

생성된 OH•가 세포 내부에 국한되어 있는 것으로 밝혀졌습니다.

이러한 연구에 따르면,

펜톤 반응에 의한 소포체[53,54]는

저산소증 유도 유전자 발현을 조절합니다.

ER 스트레스는

세포에서 합성, 접힘, 구조적 성숙을 통해 만들어지는

모든 단백질의 3분의 1 이상을 조절하는 것으로 보고되었습니다 [55].

또한,

세포 외에서 생성되는 ROS의 한 종류인

H2O2는 세포막을 쉽게 통과하여

세포 내 철(Fe2+ 및 Fe3+)과 반응하여

펜톤 반응과 펜톤 유사 반응을 통해

OH•를 생성합니다.

OH•는 1나노초보다 짧은 생체 분자와 가장 강하게 반응합니다[3,56].

이로 인해 ROS 중 생물학적 시스템에

가장 심각한 손상이 발생합니다.

분자의 산화를 유도하는 것과 관련이 있습니다.

펜톤 반응을 통해 생성된 OH•는

DNA 손상을 유발하는 것으로 보고되었습니다[57].

Hb에서 방출된 철은

또한 데옥시리보스의 분해를 촉진하여

지질 과산화를 유발하는 것으로 알려져 있습니다[58,59].

또한, 펜톤형 화학(예: 퍼옥시다아제, 유리헴, 금속 이온)은

단백질 내 티로신 잔기에서 관찰되는 티로신 니트로화에 관여하며,

퍼옥시니트라이트의 특징으로 사용됩니다 [60].

Figure 3. Typical model of reactive oxygen species generation via the Fenton reaction in a biological environment. CAT, catalase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; NADP +, oxidized form of nicotinamide adenine dinucleotide phosphate; SOD, superoxide dismutase (modified with permission from [61] under the Creative Commons CC BY 3.0 license, https://creativecommons.org/licenses/by/3.0/ (accessed on 28 July 2022)).

그림 3. 생물학적 환경에서 펜톤 반응을 통해 반응성 산소 종이 생성되는 전형적인 모델. CAT, 카탈라제; GPx, 글루타치온 퍼옥시다아제; GR, 글루타치온 환원효소; GSH, 환원형 글루타치온; GSSG, 산화형 글루타치온; NADPH, 니코틴아미드 아데닌 디뉴클레오티드 포스페이트의 환원형; NADP+, 니코틴아미드 아데닌 디뉴클레오티드 포스페이트의 산화형; SOD, 슈퍼옥사이드 디스뮤타제(Creative Commons CC BY 3.0에 따라 [61]의 허가를 받아 수정됨) 라이선스, https://creativecommons.org/licenses/by/3.0/ (2022년 7월 28일 액세스).

In heme proteins, the transition of iron is essential for the performance of their functions. Among them, cytochrome P450 is one of the largest enzyme families, in which as many as 18,000 P450s have been identified [62] and is well known to work in detoxification of drugs or other xenobiotics. This enzyme is made up of 40–50 kDa single polypeptides with a long I helix and H-bond between Cys, and a peptide NH group is regarded as the key factor to heme iron redox. Fe2+ centered in the enzyme binds to O2 to form oxy complex followed by the second electron transfer and heterolytic cleavage, during which ROS can be produced. Heme degradation catalyzed by heme oxygenases also generates ROS by non-heme iron.

Recently, ferritinophagy and ferroptosis have attracted attention as iron-dependent cell death. Ferritinophagy consists of the autophagic degradation of ferritin to regulate iron homeostasis [63]. Increased intracellular iron levels following the release from ferritin promotes ROS production, leading to cell death; radiation is reported to induce autophagic iron-dependent death in cancer cells, which is a promising therapeutic strategy [64]. “Ferroptosis”, coined by Brent Roark Stockwell and Scott Dixon in 2012 [65], is one type of regulated cell death dependent on iron or ROS, which is distinct from other types such as apoptosis, necrosis, and autophagic death at the morphological, biochemical, and genetic levels. Excessive iron in cell lines (harboring RAS mutations with increased iron uptake and decreased iron storage) induces ferroptosis, which is regulated by suppression of the master transcription factor of iron metabolism [66], indicating that ferroptosis is iron dependent. Although the correlation between autophagy and ferroptosis is not well understood, Park et al. elucidated that ROS-induced autophagy plays an important role in ferritin degradation and transferrin receptor 1 expression‎ during ferroptosis [67]. More details on ferroptosis are beyond the scope of this review and are reviewed and described by Xie et al. [68], Chen et al. [69], and Bebber et al. [70].

헴 단백질에서 철의 전이는 기능 수행에 필수적입니다. 그중에서도 사이토크롬 P450은 18,000개의 P450이 확인된 가장 큰 효소군 중 하나이며 [62] 약물 또는 기타 이종물질의 해독 작용을 하는 것으로 잘 알려져 있습니다. 이 효소는 40-50 kDa의 단일 폴리펩티드로 구성되어 있으며, 긴 I 나선과 Cys 사이의 H 결합을 가지고 있으며, 펩티드 NH 그룹은 헴 철의 산화 환원에 중요한 요소로 간주됩니다. 효소 중심에 있는 Fe2+는 O2와 결합하여 산소 복합체를 형성한 다음, 두 번째 전자 전달과 이질 분해 분열이 일어나면서 ROS가 생성될 수 있습니다. 헴 산소효소에 의해 촉매되는 헴 분해는 또한 비헴 철에 의해 ROS를 생성합니다.

최근에는 철분 의존성 세포 사멸로 페리토노파지(ferritinophagy)와 페로토시스(ferroptosis)가 주목받고 있습니다. 페리토노파지는 철분 항상성을 조절하기 위해 페리틴의 자가포식 분해로 이루어집니다 [63]. 페리틴에서 방출된 후 증가된 세포 내 철분 수준은 ROS 생성을 촉진하여 세포 사멸을 유발합니다. 방사선은 암세포에서 자가포식 철분 의존성 사멸을 유도하는 것으로 보고되어 유망한 치료 전략입니다 [64]. 2012년 브렌트 로크 스톡웰과 스콧 딕슨이 만든 “페로톡시시스(Ferroptosis)”는 철이나 ROS에 의존하는 조절된 세포 사멸의 한 유형으로, 형태적, 생화학적, 유전적 수준에서 아폽토시스, 괴사, 자가포식적 사멸과 같은 다른 유형과 구별됩니다. 과도한 철분(철분 흡수 증가 및 철분 저장 감소와 관련된 RAS 돌연변이 보유)은 철분 대사의 주요 전사 인자의 억제에 의해 조절되는 페로토시스를 유발하며, 이는 페로토시스가 철분에 의존적임을 나타냅니다[66]. 자가포식 작용과 페로토시스 사이의 상관관계는 잘 알려져 있지 않지만, 박 등(Park et al.)은 ROS에 의한 자가포식 작용이 페로토시스 동안 페리틴 분해와 트랜스페린 수용체 1 발현에 중요한 역할을 한다는 것을 밝혀냈다[67]. 페로토시스(ferroptosis)에 대한 자세한 내용은 이 리뷰의 범위를 벗어나며, 시에 등(Xie et al.)[68], 첸 등(Chen et al.)[69], 벡버 등(Bebber et al.)[70]이 검토하고 설명하고 있다.

4. Use of the Fenton Reaction for Drugs

ROS are regarded to cause intracellular lipid peroxidation, leading to ferroptosis. Therefore, the Fenton reaction has been challenged for use in directly attacking cancer cells, but it is difficult to treat them because of the low amounts of generated OH• [71]. In recent years, various nanoparticles that enhance the effectiveness of Fenton reactions for drug applications (nanomedicines) have been reported. A simple scheme is depicted in Figure 4. Previous reports on such an approach have already been well reviewed by Meng et al. [72], Ranji-Burachaloo et al. [73], and Miyazawa et al. [74], so the present review focuses on very recent reports (from 2020) on nanomedicines using the Fenton reaction.

Figure 4. Depicted representative scheme of cell apoptosis by Fe-containing nanomedicines via the Fenton reaction. DOX, doxorubicin; APAP, amionoacetophen; BSA, bovine serum albumin; HA, hyaluronic acid; SOD, superoxide dismutase; ROS, reactive oxygen species.

Xing et al. prepared an iron-loaded liposome using hollow mesoporous Prussian blue co-delivering iron, unsaturated lipids, and a photothermal converter. Controlled passive targeting enabled efficient photothermal effects and ferroptosis of these liposomes with low toxicity [75]. Tian et al. prepared ultra-small ellagic acid-Fe-bovine serum albumin nanoparticles and showed acceleration of Fe3+/Fe2+ transformation by strong reduction of endogenous H2S [76]. Sang et al. first prepared PZIF-67 nanoparticles with SOD (super oxide dismutase)-like activity and an OH -generating ability [77]. Gao et al. prepared the nanoparticles encapsulating light-responsive CO prodrugs by self-assembly of photoresponsive polymers. These nanoparticles accumulated in mitochondria and light-responsively released CO and the prodrugs, followed by the Fenton reaction, which generated high levels of ROS to decrease cell viability. Actually, intravenous injection of the nanoparticle significantly suppressed the tumor growth with an increase in ROS [78]. You et al. combined NIR irradiation with nanoparticles. Functional nanoparticles with internally encapsulated functional benzothiazole complexes (eTB2) and the photosensitizer indocyanine green induced FeTB2 release and Fenton reaction under NIR irradiation [79]. Wu et al. prepared hollow porous carbon coated with FeS2-based nanoparticles. Prepared hollow porous carbon revealed that the conversion of NIR heat into an effective temperature rise by the carbon shell and the reduction of Fe3+ to Fe2+ by tannic acid promoted the Fenton reaction [80]. Fu et al. reported that DOX and glucose oxidase-gallic acid/iron complexes were encapsulated into zeolitic imidazole framework-8 nano particles, which induced cancer cell death by the Fenton reaction with gallic acid/iron complexes under an acidic microenvironment [81]. Chen et al. reported the preparation of biodegradable nanoparticles of Fe3O4 bound with protocatechuic acid and human serum albumin loaded with β-lapachone [82].

Correlating pH or ROS sensitivity with the Fenton reaction enables more effective and selective attack of tumor cells, which is also being used as an approach. Sun et al. prepared synergistically therapeutic nanoparticles that encapsulated acetaminophen (APAP). Sun et al. prepared nanoparticles with the ability to induce the Fenton reaction in a weakly acidic tumor microenvironment. The prepared nanoparticles showed the conversion of APAP to the toxic metabolite NAPQ1, leading to GSH depletion and accelerating the effect of the Fenton reaction [83]. Zhong et al. prepared pH-responsive nanoparticles using BSA-derived albumin as carrier nanoparticles and encapsulating triphenylphosphine-modified DOX, which could be used to target tumor mitochondria [84]. Meng et al. prepared a metal-phenolic network-based multifunctional nanocomposite coated with Fe–tannic acid complexes and reported that Fe–tannic acid was degraded by laser irradiation (808 nm) and the acidic pH of the tumor environment, resulting in drug release and the Fenton reaction, promoting the effect of tannic acid [85]. Lei et al. prepared pH-responsive nanoparticles co-encapsulated with DOX and APAP, which were released at 56.5% and 61.8%, respectively, under an acidic endosomal/lysosomal environment, synergistically promoting OH• generation by the Fenton reaction [86]. Cho et al. prepared dual (pH- and redox-)responsive magnetic nanoparticles that promote drug release under low pH and high GSH concentrations [87], and Chen et al. developed a pH/ROS-responsive multifunctional nanoplatform that inhibits tumor through chemo/photodynamic/chemodynamic combinations [88]. Jia et al. prepared multifunctional nanoparticles with a core-shell structure encapsulating Fe3O4 and demonstrated that simultaneous photothermal and chemodynamic therapy is possible [89]. In addition to tannic acid, several food components have been used as effective applications for anticancer therapy as follows: the generation of ROS by vitamin C based on the Fenton reaction of Fe3O4 nanoparticles in cells [90]; promotion of lipid peroxidation and induction of ferroptosis in anaplastic thyroid carcinoma produced by vitamin C via the Fenton reaction [91]; enhancement of linomycin release by the Fenton reaction using tea polyphenols [92].

In addition to Fenton reactions, approaches utilizing the Fenton-like reaction have also been utilized. Cheng et al. reported that the Cu2+ and polymersome complex efficiently induced the Fenton-like reaction and promoted the oxidation of iminoboronates [93]. Wang et al. reported that conjugation of nanoparticles composed of glucose oxidase, Cu2-xSe, and a membrane of 4T1 cells promoted the Fenton reaction by increasing H2O2 under NIR-II irradiation [94]. Sun et al. prepared nanotubes composed of SiO and Cu, which is advantageous for the combination of photodynamic therapy and photothermal therapy (PTT). The prepared nanotubes effectively promoted the generation of ROS by the reaction between Cu2+ with H2O2 in the Fenton-like reaction, PTT effect, and porous structure of the nanotubes [95].

5. Fenton Reaction in Food

It is known that complex interactions occur between metal ions (or protein–metal ion complexes) and food components. Research on the relationship between the Fenton reaction and food components is relatively advanced in terms of flavonoids. Flavonoids are known to have antioxidative effects and are regarded as candidates that modulate the Fenton reaction. Among the flavonoids, the antioxidant/prooxidant properties of luteolin or kaempferol in Fenton-like reactions have been reported. For example, it has been reported that coordination of luteolin or kaempferol to Cu(II) significantly suppresses the generation of hydroxyl and superoxide radicals by 80% in the Fenton-like reaction [96,97]. These Cu-flavonoid complexes are considered to have intercalation activity towards DNA, which have potential applications for disorders associated with oxidative damage. Perron et al. measured the oxidation rate of Fe2+ when several polyphenol compounds were bound and found that galloyl groups oxidize iron faster than catechol groups, suggesting that a single iron-binding moiety contributes to the protective effects of polyphenols against oxidative damage [98]. Proteins are also affected by the Fenton reaction at their amino acid residues; cysteine and methionine residues are especially easily oxidized [99,100]. Bochi et al. investigated the effects of Fenton reaction-generated advanced oxidation protein products on the gene transcription in HEK293 cells [101]. As a result, it activated the gene transcription of inflammatory genes (NF-κB, COX-2, and IL-6), possibly mediating inflammation in the kidneys. Ishikawa et al. reported that phosphoprotein phosvitin, known as iron-career in egg yolk, chelated iron more effectively than other iron-binding proteins such as ferritin and transferrin, and accelerated the oxidation of Fe2+ to inhibit the Fenton reaction [102]. In some cases, the Fenton reaction may play a role in improving food quality as an effective tool. Voltea et al. used the Fenton reaction to accelerate the oxidative brewing of white wines, enabling rapid testing to assess the susceptibility, appropriate levels of flavanols and total free sulfhydryls for subsequent processes [103]. Gharib-Bibalan et al. showed that the oxidation process via the Fenton reaction modified the color and total polyphenols, improving the quality indexes of the purified juice [104]. Blank et al. reported that the Fenton-type reaction has significant effects on the aroma of coffee beverages [105]. Yeung et al. hydrolyzed okra pectin by the Fenton reaction to obtain pectic oligosaccharides with low molecular weights (1.79–6.09 kDa) and improved bioactivity (antioxidant and anti-inflammatory) [106]. Food components should also interact with metal ions in the body, but there are few reports on this.

One of the most important concerns regarding commercial food is their safety. As the Fenton reaction generates strong toxic radicals, it is used to kill bacteria that cause food poisoning. Shi et al. developed the Fenton reaction-assisted photodynamic inactivation method, a simple system that combines calcinated melamine sponges and Fe2+ to inactivate Salmonella under light illumination [107]. Morikawa et al. developed two “green” iron catalysts with reducing and chelating ability using tea leaves and coffee grounds [108]. This system with the catalytic Fenton reaction enhanced the degradation of the contaminants into harmless compounds and disinfection of Escherichia coli. In contrast, the Fenton reaction can also work as a protective system for certain microbes. Calhoun et al. reported that Dps, a ferritin-like protein with DNA-binding properties, protects Salmonella enterica serotype Enteritidis against the common killing mechanism of bactericidal antibiotics through the Fenton reaction [109]. Since oxidation leads to food deterioration, the monitoring of food conditions is essential and several approaches using the Fenton reaction have been reported. Abbas et al. developed a simple and highly sensitive fluorometric method based on the Fenton reaction system to assess H2O2 in foods [110]. Additionally, Wang et al. developed a novel colorimetric and fluorescent ELISA based on the Fenton reaction triggered by glucose oxidation was constructed to quantitatively and qualitatively measure danofloxacin in milk [111].

6. Conclusions

This review summarized the Fenton reaction from the basic principle to the bioavailability of iron, and the latest applications in the medical and nutritional fields. In the medical fields, it appears that various nanomedicines utilize the intracellular Fenton reaction as the generating system of strongly toxic OH• to enhance their selectivity and efficiency. In the nutritional fields, the Fenton reaction has been used to kill microorganisms that cause food spoilage, and this redox system has also been applied to food processing. The Fenton reaction is also useful in the synthesis of bioethanol [112,113] and the removal of pollutants derived from drugs or food additives [114,115,116,117]. Through this review, it can be inferred that the Fenton reaction can be used as a useful technology in both the medical and nutritional fields, though the mechanism is partially unknown. Additionally, the biosafety of Fenton-reaction-based nanomedicines is insufficient and unclear. Most papers regard the Fenton reaction as being useful, with less side effects than other drugs because the reaction is regulated by H2O2 and pH. However, for example, hypoxia, related to H2O2 generation, is a typical feature of solid tumors of cancer. Further investigation into the biosafety of Fenton-reaction-based treatment is warranted. It is expected that new technologies utilizing the Fenton reaction will continue to be developed.

On the contrary, it was found that the Fenton reaction of absorbed food components has been little examined to date. For example, vitamin C is one of the well-known antioxidants in the body, but it can also act as a pro-oxidant through the Fenton reaction [118]. Simultaneously, vitamin C changes into its oxidized form, dehydroascorbic acid. The mechanism by which high-level vitamin C kills cancer cells has been the subject of much debate [119], and recent studies have described the potential contribution of dehydroascorbic acid to cancer cell destruction [120,121]. This indicates the free-iron and Fenton reaction are involved in the functions of compounds with reduction properties, but their interaction has rarely been examined. As the redox system is too complicated in the body system, a comprehensive understanding might be necessary to elucidate the rules of their bioactivities. As science and technology advance in general, there will be a demand for a more sufficient understanding of the effects of these food components and Fenton reactions. More progress is expected in the near future.

Author Contributions

Conceptualization, C.A. and T.M. (Taiki Miyazawa); writing—original draft preparation, C.A.; writing—review and editing, T.M. (Taiki Miyazawa); supervision, T.M. (Teruo Miyazawa). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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