**Redox Reactions in the Physiopathology of the Liver**

**Redox Reactions in the Physiopathology of the Liver**

DOI: 10.5772/intechopen.68841

Isabel Méndez, Francisco Vázquez‐Cuevas, Rolando Hernández‐Muñoz, Héctor Valente‐Godínez, Olivia Vázquez‐Martínez and Mauricio Díaz‐Muñoz Rolando Hernández‐Muñoz, Héctor Valente‐ Godínez, Olivia Vázquez‐Martínez and Mauricio Díaz‐Muñoz Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Isabel Méndez, Francisco Vázquez‐Cuevas,

http://dx.doi.org/10.5772/intechopen.68841

#### **Abstract**

Electron fluxes are constant within cellular metabolism. Donating or accepting electrons, either naked or as hydrogen atoms, is one of the most important properties of bioen‐ ergetic networks. These redox reactions fulfill key physiological phenomena such as cellular growing, phenotypic differentiation, nutritional adaptations and redox‐depen‐ dent cellular signaling, but when they became unregulated, serious pathologies such as degenerative diseases and metabolic disorders arise. The liver being an important meta‐ bolic organ, redox reactions play a strategic role in its main functions: processing of nutri‐ ents, fasting response, xenobiotic managing and circadian activity. However, liver is also very sensitive to compounds that disturb redox state such as ethanol, CCl<sup>4</sup> , aflatoxins, among others, as well as to stressors such as hypercaloric diets, endocrine disruptors and stressful life situations. This chapter reviews concepts related to redox reactions in the liver, including metabolic aspects of reactive oxygen species (ROS), prooxidant and antioxidant subcellular systems, alterations produced by hepatotoxins, adaptations to experimental surgical protocols such as portacaval anastomosis, and participation in can‐ cer. It is out of question that for a better comprehension of the physiopathological events in the liver and other metabolic organs, the more complete understanding of the roles played by redox reactions will be a necessity.

**Keywords:** metabolism, ROS, antioxidant, prooxidant, hepatocyte

## **1. Introduction**

Living organisms are dynamic and complex systems with the notable capacity to continu‐ ously preserve their structural identity, but at the same time, to display functional and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

morphological adaptations in daily terms (circadian rhythms), during ontogeny, as well as in the context of evolutionary progression. Since living beings are thermodynamic open sys‐ tems, they are empowered to exchange matter and energy. This competence sustains the intri‐ cate intertwine that make up the metabolic networks present in every cell [1].

For the last 2 billion years (after the transition of oxygenic photosynthesis), in our planet the bioenergetic cycle has been defined by two principal and complementary processes: pho‐ tosynthesis and respiration [2]. Indeed, every other chemical and energetic transformation that takes place in the cellular milieu is included within this biochemical cycle (**Figure 1**). Inspection of the formula shown in **Figure 1** rapidly indicates that carbon‐containing mol‐ ecules oscillate from a reduced (as glucose) to an oxidized state (as carbon dioxide). The corollary is that in a general sense, metabolism can be visualized as a collection of reduction‐ oxidation (redox) reactions [3].

Electrons flux is in the pith of the formal definition of redox reactions: it establishes that mol‐ ecules accepting electrons are reduced whereas those that give up electrons are oxidized. Therefore, redox reactions always occur between redox pairs. As Albert Szent‐Gyorgyi, the prestigious Nobel Prize winner biochemist in 1937, quoted: (1) understanding metabolism is to figure out the direction taken by the electrons in transit among molecules and (2) the secret of life is to take advantage of the correct flow of the electrons [4]. Electrons in transit can be mobilized alone (as in the iron‐sulfur complexes and cytochromes within mitochondrial and microsomal electron transport chains) or joined with protons as hydrogen atoms (as in bio‐ chemical transformation among acids, aldehydes and alcohols).

Redox potential (Δ*E*, quantified in volts) is a physicochemical parameter that measures the capacity to either release or accept electrons within a chemical reaction. It characterizes the extent of free Gibbs energy (Δ*G*) and the direction of the electron flow in each redox reaction (Δ*G* = *nF*Δ*E*, *n* is the electrons transferred and *F* is Faraday's constant). Molecular entities with higher (more positive) redox potential have the facility to oxidize molecules with a lower (more negative) redox potential [5]. Spontaneous biochemical transformations involve the release of metabolic energy as the electrons move from reactions with negative redox poten‐ tial (oxidation of glucose into 2 pyruvates + 4e− , −720 mV) to reactions with positive redox potential (reduction of O2 with 2e− into water, +820 mV).

#### **1.1. Liver as a paradigmatic metabolic organ**

Certainly, every cell and tissue in the organism shows metabolic activity. However, the liver has a special consideration since it is the principal organ in the biochemical processing of nutrients and xenobiotics. Distinctive metabolic pathways, such as gluconeogenesis, ureagen‐ esis, assembly of lipoproteins, synthesis of ketone bodies, metabolism of foreign chemical substances, lipogenesis, cholesterol formation, glutamine synthesis, and others, take place in the different population of hepatocytes: periportal (with high [O2 ] and oxidative metabolism) and pericentral (with low [O2 ] and less oxidative metabolism) [6].

Hepatic metabolism comprises synthetic (anabolic) and degradative (catabolic) pathways, each one being regulated by particular factors, including: (1) cellular compartments (oxidative

Redox Reactions in the Physiopathology of the Liver http://dx.doi.org/10.5772/intechopen.68841 157

morphological adaptations in daily terms (circadian rhythms), during ontogeny, as well as in the context of evolutionary progression. Since living beings are thermodynamic open sys‐ tems, they are empowered to exchange matter and energy. This competence sustains the intri‐

For the last 2 billion years (after the transition of oxygenic photosynthesis), in our planet the bioenergetic cycle has been defined by two principal and complementary processes: pho‐ tosynthesis and respiration [2]. Indeed, every other chemical and energetic transformation that takes place in the cellular milieu is included within this biochemical cycle (**Figure 1**). Inspection of the formula shown in **Figure 1** rapidly indicates that carbon‐containing mol‐ ecules oscillate from a reduced (as glucose) to an oxidized state (as carbon dioxide). The corollary is that in a general sense, metabolism can be visualized as a collection of reduction‐

Electrons flux is in the pith of the formal definition of redox reactions: it establishes that mol‐ ecules accepting electrons are reduced whereas those that give up electrons are oxidized. Therefore, redox reactions always occur between redox pairs. As Albert Szent‐Gyorgyi, the prestigious Nobel Prize winner biochemist in 1937, quoted: (1) understanding metabolism is to figure out the direction taken by the electrons in transit among molecules and (2) the secret of life is to take advantage of the correct flow of the electrons [4]. Electrons in transit can be mobilized alone (as in the iron‐sulfur complexes and cytochromes within mitochondrial and microsomal electron transport chains) or joined with protons as hydrogen atoms (as in bio‐

Redox potential (Δ*E*, quantified in volts) is a physicochemical parameter that measures the capacity to either release or accept electrons within a chemical reaction. It characterizes the extent of free Gibbs energy (Δ*G*) and the direction of the electron flow in each redox reaction (Δ*G* = *nF*Δ*E*, *n* is the electrons transferred and *F* is Faraday's constant). Molecular entities with higher (more positive) redox potential have the facility to oxidize molecules with a lower (more negative) redox potential [5]. Spontaneous biochemical transformations involve the release of metabolic energy as the electrons move from reactions with negative redox poten‐

into water, +820 mV).

Certainly, every cell and tissue in the organism shows metabolic activity. However, the liver has a special consideration since it is the principal organ in the biochemical processing of nutrients and xenobiotics. Distinctive metabolic pathways, such as gluconeogenesis, ureagen‐ esis, assembly of lipoproteins, synthesis of ketone bodies, metabolism of foreign chemical substances, lipogenesis, cholesterol formation, glutamine synthesis, and others, take place in

] and less oxidative metabolism) [6]. Hepatic metabolism comprises synthetic (anabolic) and degradative (catabolic) pathways, each one being regulated by particular factors, including: (1) cellular compartments (oxidative

, −720 mV) to reactions with positive redox

] and oxidative metabolism)

cate intertwine that make up the metabolic networks present in every cell [1].

chemical transformation among acids, aldehydes and alcohols).

tial (oxidation of glucose into 2 pyruvates + 4e−

**1.1. Liver as a paradigmatic metabolic organ**

with 2e−

the different population of hepatocytes: periportal (with high [O2

potential (reduction of O2

and pericentral (with low [O2

oxidation (redox) reactions [3].

156 Redox - Principles and Advanced Applications

**Figure 1.** Global energy flux underlying redox cycle between photosynthesis and respiration. Driving by solar energy, autotrophic organisms synthetize biomolecules (carbohydrates for example) and oxygen by photosynthesis. Heterotrophic organisms oxidize carbohydrates to yield carbon dioxide and water by respiration. The cycle is complete when carbon dioxide and water are used again by autotrophic organisms.

reactions are preponderant in mitochondria and peroxisomes whereas reductive reactions are more common in cytosol), (2) available coenzymes (oxidized nicotinamide adenine dinucleo‐ tide (NAD+ ), reduced nicotinamide adenine dinucleotide (NADH) for catabolism and oxi‐ dized nicotinamide adenine dinucleotide phosphate (NADP+ ), reduced nicotinamide adenine dinucleotide phosphate (NADPH) for anabolism), (3) adenine nucleotides pool (low energy charge, AMP‐activated protein kinase (AMPK) activation for catabolism and high energy charge, reduced AMPK activity for anabolism) [7].
