Open access peer-reviewed chapter

Cholestasis: The Close Relationship between Bile Acids and Coenzyme Q10

Written By

Manuela R. Martinefski, Silvia E. Lucangioli, Liliana G. Bianciotti and Valeria P. Tripodi

Submitted: June 25th, 2019 Reviewed: December 11th, 2019 Published: December 30th, 2019

DOI: 10.5772/intechopen.90831

From the Edited Volume

Hepatitis A and Other Associated Hepatobiliary Diseases

Edited by Costin Teodor Streba, Cristin Constantin Vere, Ion Rogoveanu, Valeria Tripodi and Silvia Lucangioli

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Abstract

Cholestasis is defined as the impairment in formation or excretion of bile from the liver to the intestine. It may result from defects in intrahepatic production of bile, impairment of hepatic transmembrane transporters, or mechanical obstruction to bile flow. In cholestasis, hepatocytes are exposed to high levels of bile acids, particularly those bearing hydrophobic properties. The increase in bile acids induces oxidative stress, leading to an imbalance in the prooxidant:antioxidant ratio which determines the final cellular redox status. This chapter will focus on the close relationship between bile acids and the most powerful endogenous antioxidant, coenzyme Q10 in cholestasis, and the eventual alternative therapeutic option of CoQ10 supplementation to current traditional therapies.

Keywords

  • cholestasis
  • coenzyme Q10
  • bile acids

1. Cholestasis: types, clinical presentation, diagnosis and current therapeutic approaches

Bile is a nonenzymatic secretion produced by hepatocytes. The main components of bile include bile salts necessary for enzymatic fat digestion and absorption, bilirubin, and cholesterol. Drugs and other xenobiotics are also excreted into bile following hepatic metabolization. Bile flow is dependent on the active canalicular transport of bile acids and other substrates mediated by the bile salt export pump (Bsep), which transports osmotically active monoanionic bile salts into the bile canaliculus and multidrug resistance-associated protein 2 (Mrp2), which exports oxidized and reduced glutathione. Bile secreted by the hepatocytes is stored and concentrated in the gallbladder, which contracts in the presence of the hormone cholecystokinin resulting in bile release into the duodenum through the cystic and common bile duct.

Cholestasis is defined as the decrease or suppression of bile flow due to impaired secretion by hepatocytes or to obstruction of bile at any level of the excretory pathway, from the hepatocyte canalicular membrane to the ampulla of Vater in the duodenum. Cholestasis leads to the retention of the major constituents of bile, bilirubin, and bile acids, in blood. By convention, cholestasis is chronic when it lasts more than 6 months. Prevalence of cholestasis is not significantly different between males and females. Nevertheless, women are at lighter risk of developing drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Despite that, cholestasis may affect people of every age group, newborns and infants are more prone due to the immaturity of the liver.

The morphologic features of cholestasis are dependent on the severity, duration, and the underlying cause. Cholestasis is classified as intrahepatic or extrahepatic cholestasis depending on the cause that leads to impaired bile flow. Intrahepatic cholestasis is due to a disease affecting the hepatocytes and/or the intrahepatic bile ducts, whereas extrahepatic cholestasis or obstructive cholestasis results from the obstruction of the extrahepatic biliary ducts.

Obstruction of bile ducts can be caused by gallstones, cysts, stenosis, or tumors. The most frequent causes of extrahepatic cholestasis in adults include cholelithiasis and malignancies of the biliary tree or the head of the pancreas. However, in children, biliary atresia and cystic fibrosis are the main causes. Intermittent or partial obstruction may lead to ascending cholangitis, a secondary bacterial infection of the biliary tree. The typical morphological changes are reversible if the obstruction is corrected, but if it persists it can lead to biliary cirrhosis.

Causes of intrahepatic or hepatocellular cholestasis include viral and autoimmune hepatitis, inborn errors of bile acid synthesis, primary biliary cirrhosis, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, total parenteral nutrition, and drug toxicity. The drug class mostly implicated in cholestasis is antibiotics. However, anti-inflammatory drugs, highly active antiretroviral therapy, psychotropes, some chemotherapy agents, oral contraceptives, and anabolic steroids have also been reported to cause cholestasis [1]. Although primary sclerosing cholangitis affects intrahepatic bile ducts, it can also affect extrahepatic bile ducts.

Clinical presentation of cholestasis includes jaundice, pruritus, skin xanthomas, or symptoms associated with intestinal malabsorption. Jaundice and pruritus are present in all types of cholestasis whether acute or chronic, whereas the other clinical features are more associated with chronic cholestasis.

Jaundice is the clinical expression of bilirubin retention. Excretion of conjugated bilirubin is the rate-limiting step of bilirubin clearance. During cholestasis, conjugation of bilirubin continues but the excretion is significantly reduced. Jaundice is observed by scleral icterus at a concentration as low as 2 mg/dL accompanied by dark urine. The concentration of conjugated bilirubin in blood depends on its production rate and excretion pathways, as well as cholestasis degree. Non conjugated bilirubin is also increased in patients with cholestasis. The magnitude of the increase in serum bilirubin concentration does not correlated with the type or severity of cholestasis. Pruritus is a frequent clinical manifestation of cholestasis, which has been long associated with increased serum bile acids. However, its origin is multifactorial and diverse studies show that not only bile acids but also lysophosphatidic acid, and bilirubin are potential mediators of cholestatic itch [2]. Retention of bile acids and their conjugated salts results in biological membrane injury, particularly in the liver due to their detergent properties. Increased hydrophobic bile salts favor their incorporation into membranes, altering membrane fluidity and function. Enhanced secondary bile acids like lithocholic acid result in further membrane injury. The transport of bile salts from plasma to bile is the principal driving force for bile formation and it is mediated by several hepatic transporters, mostly belonging to the ABC family of transporters. Numerous studies support that the failure to excrete bile salts into the canaliculus is the main mechanism underlying cholestasis. In this sense retrieval of the canalicular transporters Bsep and Mrp2 from hepatocyte plasma membrane to endosomal compartments in different types of cholestasis has been well documented [3, 4]. However, other works consider that the endocytic retrieval of canalicular transporter is the result of cholestasis on the hepatocyte function. In either case, the retention of bile salts in the liver induces down-regulation of bile acid synthesis, overall reduction in the total pool size and damage to hepatocytes.

Skin xanthomas and signs of malabsorption are associated with chronic cholestasis. Skin xanthomas result from focal accumulation of cholesterol in the dermis and usually appear around the eyes, but may be present in other parts of the body. Malabsorption occurs due to the failure of enough bile salts to reach the duodenum, so the digestion and absorption of dietary fat is impaired. Fat soluble vitamins like A, E, D, and K are poorly absorbed in cholestasis leading to clinical symptoms and signs of their deficiency.

In all types of cholestasis, characteristic laboratory findings are elevated serum alkaline phosphatase and γ-glutamyltranspeptidase, enzymes present on the canalicular membranes of hepatocytes, and bile duct epithelial cells. Alkaline phosphatase is also elevated in bone growth or disease, pregnancy, or intestinal diseases. λ-Glutamyltranspeptidase is a sensitive marker of cholestasis [5], although no specific since it can be elevated in other liver diseases [6]. Furthermore, its elevation may reflect enzyme induction by drugs or alcohol. Serum 5′-nucleotidase, an enzyme located in canalicular membranes and lining the sinusoids is also elevated in cholestasis, although it appears to be less sensitive than alkaline phosphatase. Serum elevation of hepatic enzymes is accompanied by increased serum bilirubin and bile acids. An increase in serum bile acids is an early marker of cholestasis.

In the diagnosis of cholestasis, the first key step is to identify whether it is intrahepatic, extrahepatic, or both. The patient history and physical examination usually provide useful information. Elevation of both hepatic enzymes (alkaline phosphatase and λ-glutamyl transpeptidase) is a hallmark of cholestasis although the identification of the type of cholestasis requires imaging studies and additional biochemical studies. Imaging studies include first an abdominal ultrasonography to exclude dilated intra and extrahepatic ducts. When bile duct alterations are observed, further imaging studies like magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography should be performed. A diagnostic of intrahepatic cholestasis can be made when imaging studies exclude mechanical obstruction. Then, further biochemical studies are necessary to identify the intrahepatic cause of cholestasis, including liver biopsies when the diagnosis is unclear.

The therapeutic intervention for cholestasis may differ depending on the etiology [7]. Based on controlled clinical trials, ursodeoxycholic acid (UDCA) is the treatment of choice for diverse cholestatic disorders like primary biliary cirrhosis and intrahepatic cholestasis of pregnancy due to its anticholestatic properties. However, UDCA treatment is not so effective in other cholestatic disorders like in primary sclerosing cholangitis. No therapy of proven benefit for the long-term prognosis of genetic cholestatic liver disease exists. In drug-induced cholestasis, withdrawal of the drug is the only effective treatment [8]. Pruritus is a common manifestation of cholestasis, which can be of serious severity. Management of pruritus includes cholestyramine as first line-treatment and then rifampicin, and opiate antagonists [9].

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2. Bile acids: physicochemical properties, synthesis, and therapeutics

2.1 Bile acids physicochemical properties

Bile acids (BA) are steroid compounds, hydroxyl derivatives of 5β-cholan-24 oic acid. Primary BA are cholic acid (CA) and chenodeoxycholic acid (CDCA); secondary BA such as deoxycholic acid (DCA) and lithocholic acid (LCA), all of them in 3α-position, and ursodeoxycholic acid (UDCA) is a hydroxyl derivative in 3β-position (Figure 1) [10].

Figure 1.

Bile acids: chemical structure.

BA have different physicochemical properties according to the number, position, and orientation of their hydroxy groups and the conjugation with glycine and taurine (Figure 1). In this sense, this characteristic influence their solubility, detergency, and hydrophobicity [11].

BA have an important role in biological systems under physiological and pathological conditions [12]. Their functions are associated with lipid digestion and absorption, solubilization of cholesterol and bile formation. In this case, BA influence in volume and composition of the bile.

The number, position, and orientation of the hydroxy groups of the BA impact directly on the hydrophobicity and detergency property and the relationship to the toxicity. In the case of BA with hydroxy groups in 3-α position, the higher the number of hydroxy groups, less hydrophobicity and lower detergency and, as a result, lower toxicity.

It must be pointed out that the orientation of the hydroxy group rules over the properties in the molecule. This can be seen on the CDCA (7α) and its epimer, the UDCA (7β), where the UDCA showed a strong reduction of detergency and hydrophobicity. Also, the BA toxicity is directly related to its hydrophobicity and detergency, because those interact with the cellular membranes in different ways, including the union, the insertion in the lipidic bilayer and its solubilization increasing its fluidity [10].

Therefore, UDCA is administered as therapeutic agent for the treatment of hepatobiliary disorders such as cholestasis, biliary dyspepsia, primary biliary cirrhosis, and different cholestatic conditions.

2.2 Bile acids synthesis

The synthesis of BA is produced exclusively in the liver, based on a series of enzymatic reactions in the hepatocyte, in which 17 enzymes are involved. The cholesterol (hydrophobic compound) turns into the primary BA, also known as colic acid (CA) and chenodeoxycholic (CDCA), through the first step and limiting of the called “classic” or “neutral” way of the BA biosynthesis, where the hydroxylation of the cholesterol is produced, catalyzed by the enzyme cytochrome P450 cholesterol 7a-hydroxylasa (CYP7A1). The BA synthesis can also occur through an “alternative” or “acidic” way, where the CYP27A1 intervenes and changes the BA oxysterols. Unlike the CYP7A1, the CYP27A1 is not regulated by the BA and is estimated only the 6% of the synthesis of BA is produced through this way. Before its secretion in the canalicular biliary light for the storage in the biliary gold bladder as mixed micelles with phospholipids and cholesterol, the primary BA are mainly conjugated with taurine and glycine, forming the conjugated BA, that with the Na+ and K+ form the biliary salts. When ingesting a food, the contraction of biliary gold bladder expels the micellar BA to the intestinal light to help digestion. In the gut, the intestinal bacteria deconjugate and dehydroxylate the primary BA, resulting in other species, denominated secondary BA: deoxycholic acid (DCA), a CA derivative, and ursodeoxycholic acid (UDCA), a CDCA derivative. The enterohepatic circulation allows the 95% of the BA to be reabsorbed from the distal ileum and transported back to the liver through portal circulation. Only 5% of the BA are not reabsorbed and are eliminated through feces. This small amount of loss is recovered through the novo synthesis of the BA in the liver. The size of the BA reserve is strictly regulated by the liver and gut to avoid a cytotoxic accumulation. When the reserve of BA increases, a feedback mechanism is activated, ruled by the interaction of several nuclear receptors, mainly the farnesoid X nuclear receptor (FXR) to inhibit the novo synthesis of BA. Therefore, the FXR is a “BA sensor,” when the BA are joined to this receptor, they mediate their own synthesis control to provide a strict regulation of its reserve [13, 14, 15].

2.3 Bile acid therapy in hepatobiliary disease: role of UDCA

BA as therapeutic agent are appropriated in the chronic cholestasis deceases. BA can be orally administered following two strategies, the “displacement therapy” and/or “replacement therapy.” UDCA may be used to displace endogenous BA to decrease the intrahepatic concentration of potentially cytotoxic BA accumulated in cholestasis. On the other hand, primary BA such as cholic acid (CA) might be used to replace a depleted BA pool resulted from defective biosynthesis on consequence to restore the physiological function of BA [16, 17].

UDCA (3α-7β-hydroxy-5β-cholan-24-oic acid) is naturally occurring BA, that normally constitutes 1–2% of the BA in human bile. UDCA is obtained by 7α-epimerization of the primary BA chenodeoxycholic acid (CDCA), by intestinal bacteria. [18] UDCA and CDCA differ in the hydroxyl group orientation at seventh position, allowing higher hydrophilicity of UDCA in comparison to CDCA.

UDCA is a weak acid (pKa = 5), and poorly water soluble, however, its solubility increases directly to the increase of the solution pH. After orally administrations, UDCA must be solubilized in mixed micelles present in small intestinal content in order to allow absorption [19, 20]. During the cholestasis disease, the UDCA bioavailability is limited due to the reduction of endogenous BA micelles in the duodenal lumen. Unconjugated UDCA is absorbed by passive diffusion in the proximal jejunum and in the ileum, thus extracted from portal venous blood by the liver and conjugated with glycine or taurine. Conjugated UDCA is secreted into the bile.

It is worth mentioning that in the UDCA oral administration, the half-life of the UDCA in the portal circulation is short, thus the maximum concentrations in liver/bile achieved by dividing the dose equally over 24 h are adequate.

UDCA is the BA of choice in view of the proven efficacy and lack of side effects in the treatment of cholestasis diseases. In the case of CDCA, its inherent toxicity is related to the fact that CDCA undergoes bacterial conversion dihydroxylation to a toxic, monohydroxy BA, like lithocholic acid (LCA), unlike UDCA, which is more resistant to bacterial dihydroxylation [21, 22].

The versatility presented by UDCA in the treatment of cholestatic diseases is due to its multiple action mechanisms:

  • Biliary stones dilution

  • Changes in the BA reserve hydrophobicity level

  • Protection against the cellular death induced by cytotoxic BA

  • Modulation of the expression of the transporters and the liver’s enzymatic systems

  • Normalization of the altered cellular location of hepatocellular transporters

  • Immunoregulatory effects

2.3.1 Biliary stones dissolution

UDCA reduces the content of cholesterol in the bile by reducing the hepatic synthesis of cholesterol and its absorption by the gut itself. In addition to solubilizing the cholesterol into micelles, it causes the cholesterol to scatter into liquid crystals in an aqueous medium causing a favorable environment for the dissolution of biliary stones. In addition to this, reduces the viscosity and improves the bile flow.

2.3.2 Changes in the BA reserve levels of hydrophobicity

In the cholestasis, the increase of hydrophobic BA produces the cytolysis of plasmatic membrane. In normal individuals, the UDCA represents not more than 4% of the complete endogenous BA reserve. Under a treatment with UDCA, this percentage increases to 40–60% under a conventional dosage of 13–15 mg/kg/day, becoming the UDCA the predominant BA, which shifts the more hydrophobic endogenous BA. Therefore, the substitution of the potentially toxic hydrophobic endogenous BA in the total BA group to a hydrophilic turns the bile more hydrophilic and less cytotoxic, reducing the hepatic lesion.

2.4 UDCA and oxidative stress

It has been proposed that UDCA antioxidative action is due to the induction of glutathione (GSH) synthesis and in this way, mitochondrial injury apoptosis is prevented [23]. UDCA activates the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and induces the translocation of nuclear factor-E2-related factor 2 (Nrf2) into the nucleus. Hence, it could be hypothesized that UDCA increases the gene expression of enzymes associated with GSH synthesis and induces the down-regulation of intracellular ROS levels [24]. In a similar fashion, insulin reduces oxidative stress by the activation of PI3K and extracellular signal-regulated protein kinase in HepG2 cells [25]. Therefore, both UDCA and insulin may exert a cytoprotective effects against oxidative stress and. Noteworthy, UDCA may reduce fatty acids-induced insulin resistance.

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3. Coenzyme Q10: generalities, clinical approaches and its relation to intrahepatic cholestasis of pregnancy

Coenzyme Q (CoQ) is an endogenous lipophilic compound synthetized in all tissues and cells. The biosynthetic pathway of CoQ in eukaryotes has been characterized by studies of mutants deficient in CoQ in Saccharomyces cerevisiae. The biosynthesis of CoQ initiates with the hydroxybenzoic acid to which a polyisoprenoid lipid tail is attached. Thus, CoQ is the product of two different converging biosynthetic pathways: the synthesis of 4-hydroxybenzoate, derived from the metabolism of tyrosine and the synthesis of the isoprene side chain that begins with the conversion of acetyl-coenzyme A (CoA) through the mevalonate route and regulated by the HMG CoA reductase. Formerly, the trans-prenyl transferase catalyzes the condensation of farnesyl pyrophosphate with numerous trans isopentenyl pyrophosphates, to form the long isoprenoid chain. Finally, these two pathways converge in a terminal step, where 4-hydroxybenzoate and polyprenyl pyrophosphate are linked by a condensation reaction catalyzed by the enzyme polyprenyl 4-hydroxybenzoate transferase [26].

Due to its ubiquitous distribution, CoQ is also called ubiquinone. In mammals, ubiquinone contains a 2,3-dimethoxy-5-methylbenzoquinone core with, predominantly, a hydrophobic 10 isoprenyl units, so it is designated as coenzyme Q10 (CoQ10, Figure 2).

Figure 2.

Coenzyme Q10: (A) oxidized form and (B) reduced form.

CoQ10, mainly placed in the inner mitochondrial membrane, plays its principal role in promoting the electron transfer from complexes I and II to complex III within the mitochondrial respiratory chain to finally obtain cellular energy [27]. Taking into account its redox properties, CoQ10 also acts as a potent lipophilic antioxidant, scavenging oxygen reactive species, protecting lipids, protein, and cellular DNA and being involved in multiple steps of vital cellular metabolism such as the electron transfer in plasmatic membranes [28] and lysosomes [29], modulation of apoptosis [30, 31] and proton transport between uncoupled proteins [32]. CoQ10 also has an important intracellular signaling role in modulating the mitochondrial permeability transition pore [33].

Although its biosynthesis is not completely dilucidated, it is well known that different mutations in some genes which codify for proteins within its biosynthetic pathway have been identified. These mutations define the primary CoQ10 deficiencies [34, 35, 36, 37, 38, 39, 40]. At this time, from the 13 known CoQ genes direct or indirect related to CoQ biosynthesis, it is recognize that eight of them can cause CoQ10 deficiency and disease [41]. Primary CoQ10 deficiencies are a group of rare diseases of clinically heterogeneous appearance suggesting an autosomal recessive inheritance, because relatives are often affected, whereas parents are characteristically unaffected. The four most frequent clinical phenotypes associated with primary CoQ10 deficiencies are encephalomiophaty, cerebellar ataxia, multisystemic infantile form, and glomerulophaty and myophaty, all of them having a muscular and neurologic compromise [27]. Patients affected with primary CoQ10 deficiency, although its clinical severity, highly respond to CoQ10 supplementation being most effective the sooner the treatment begins [35, 42].

On the contrary, secondary CoQ10 deficiency is more frequent and of less severe clinical presentation. However, its treatment only ameliorates the symptoms although improve life quality. Secondary CoQ10 deficiency is associated to different pathologies such as neuro-muscular degenerative pathologies, cardiovascular, thyroid and reproductive diseases as well as cancer among others [43, 44, 45, 46]. Coenzyme Q10 deficiency is commonly found associated to mitochondrial oxidative phosphorylation impairment, probably as an adaptive mechanism to maintain a balance in mitochondrial redox status. However, in spite of the high incidence of secondary CoQ deficiencies, the precise mechanisms underlying these secondary deficiencies remain unidentified specially in non-mitochondrial oxidative phosphorylation disorders [47].

What is certain is that final cellular CoQ10 concentration is related to the balance existing between biosynthetic and dietary supply on one side and energetic consumption on the other [48].

In a previous work, we have demonstrated a reduced plasmatic level of CoQ10 in mothers with intrahepatic cholestasis of pregnancy (ICP) as well as in an animal model, being the first report connecting CoQ10 deficiency to this disorder [49]. Later, it was confirmed in another study, which analyzed fetal CoQ10 levels in cord blood from ICP mothers [50]. It is well known that ICP is a high-risk pregnancy disease characterized by the accumulation of total serum bile acids, with an enhanced proportion of the hydrophobic bile acids which are highly cytotoxic. During the last decade, it was found many evidences suggesting that hydrophobic bile acids increase is responsible for the higher oxidative stress observed in ICP [51, 52, 53]. Thus, it was reasonable to suspect that CoQ10 levels could be diminished, secondary to the oxidative stress and/or mediated by a metabolic feedback [50]. Furthermore, a depleted CoQ9 levels (the predominant form of ubiquinone in rodents) was also observed in plasma, brain and muscle in a cholestatic rat model together with a positive correlation between CoQ9 and ursodeoxycholic/lithocholic acid ratio (UDCA/LCA). The latter suggests that increased plasma LCA may be closely related to CoQ9 decrease in blood and tissues [49].

CoQ10 decrease in ICP possibly reveals a disturbance on the delicate balance between oxidative stress and antioxidant defenses, thus accumulating large amounts of free radicals, imparing energy production, and increasing risk for the fetus. Although the relationship between CoQ10 and serum bile acids is not well established, it is possible that reduced CoQ10 levels result from enhanced ubiquinone extraction from blood because of higher cellular demand. As it was previously mentioned, it is also probable that CoQ10 depletion may be caused by increased proportion of circulating and intracellular hydrophobic bile acids and enhanced consumption of the CoQ10 by free radicals and/or a metabolic down regulation. The relationship between CoQ and bile acids will be discussed in the next section.

Since CoQ10 is a potent antioxidant and is even proposed as the first line of defense against oxidative insult [54], its tissue distribution and plasma levels will be dependent on its susceptibility to the oxidative stress induced by cholestasis.

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4. Bile acids and coenzyme Q10: possible relationship

Several studies have provided evidence that oxidative stress may play an important role in the pathogenesis of hepatic injury in animal models of cholestasis [52, 55, 56, 57, 58] and in humans [59, 60, 61].

Hepatic mitochondria have been proposed as the most important cellular source of reactive oxygen species (ROS) induced by bile acids (BA). Hydrophobic BA impair respiration and electron transport in hepatic mitochondria. Krähenbühl et al. reported that hydrophobic BA decrease the activities of several enzyme complexes involved in the electron transport chain, such as complexes I, III, and IV but not affected complex II in isolated rat liver mitochondria. Furthermore, hydrophobic BA decrease the mitochondrial membrane potential developed upon succinate energization and decrease state three and enhance state four in mitochondria [62].

Yerushalmi et al. [63] proposed that ROS are generated at the ubiquinone-complex III interaction of the respiratory chain in hepatic mitochondria upon exposure to BA. Additionally, Botla et al. [64] reported that hydrophobic BA initiates the membrane permeability transition in hepatic mitochondria. In this context, oxidative stress results from an imbalance between increased free radical and impairment of antioxidant systems.

Therefore, the link between BA and CoQ has recently achieved clinical relevance and open to potential therapeutics challenges. As it was aforementioned, a study with a validated animal model of ICP, which shows similar biochemical hepatic alterations as observed in ICP patients, showed a significant decrease in CoQ9 and α-tocopherol in plasma that correlated negatively with the increase in LCA levels in the animal model of ICP [49]. Stocker and Bowry reported that CoQ acts earlier than α-tocopherol in the antioxidant system, thus the reduction of plasmic CoQ could be considered as an early marker of oxidative insult [54]. The decrease in these antioxidants may contribute to increase oxidative stress in ICP [49]. CoQ plasmatic levels more likely reflect the degree of metabolic request; in this case decreased levels may be related to consumption by free radicals or by increasing cellular demand. On the other hand, tissue CoQ levels are related to the balance between biosynthesis, dietary supply and energetic consumption [48]. The increase in BA has different effect over CoQ tissue levels. It was observed that skeletal muscle and brain were more susceptible to oxidative stress and showed a decrease in CoQ levels in ICP animals, whereas liver and heart content of CoQ remained unchanged. An hepatic paradox described in animal model of cholestasis including EE cholestasis, where the activity of HMG-CoA reductase and 7 alpha hydroxylase is increased despite the increase of BA, could possible explain this finding [65, 66, 67, 68]. Thus, taking into account, that CoQ is synthesized via HMG-CoA reductase, it is possible that levels were maintained by an increase in its synthesis [49].

In accordance with those results, a significant decrease in CoQ10 and vitamin E levels was also observed in ICP patients respect to control pregnancies, coupled to an increase in total serum BA with a more hydrophobic profile [49]. It is worth mentioning that neonates are highly susceptible to oxidative damage caused by ROS, since the extrauterine environment is richer in oxygen than the intrauterine environment [69]. This problem is further aggravated by the low efficiency of natural antioxidant systems in the neonate that could be worsened if the antioxidant capacity of mother is deficient [48]. In addition, the direction of placental BA gradient, in normal pregnancy occurs from the fetus to the mother in order to promote toxic compounds elimination from the fetal compartment, while in ICP, this gradient is inverted allowing to accumulate BA in the fetal compartment [70, 71]. Thus, decreased CoQ10 levels in mothers with ICP may pose a risk for the newborn.

Recently, another study which evaluates umbilical cord blood of newborn from ICP mothers showed a decrease in cholesterol normalized CoQ10 content and an increase in total serum BA respect to normal pregnancy [50]. The results obtained by Martinefski et al. demonstrated a highly prooxidant environment.

Nowadays, since the relationship between CoQ and BA is not well established, two explanations have been hypothesized. On one hand, during ICP, cholesterol levels could possibly be maintained due to a mevalonate pathway deviation flow that absorbs another branch of the metabolic flow including those required to support CoQ synthesis [72].

On the other hand, hydrophobic BA stimulate the generation of ROS leading to a consumption of different antioxidants, including CoQ. Both scenarios led to a secondary CoQ deficiency.

In the field of cholestasis therapeutics, CoQ10 synthetic analog (idebenone) has shown to prevent BA stimulation of ROS from hepatic mitochondria and isolated hepatocytes [63]. Therefore, taking into account the deficiency of CoQ found in ICP, supplementation with CoQ10 could represent a new complementary therapeutic proposal for ICP in order to protect both the mother and the newborn. However, further studies are required to obtain a deeper conclusion.

References

  1. 1. Fernández-Murga LM, Petrov PD, Conde I, Castell JV, Goméz-Lechón MJ, Jover R. Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems. Food and Chemical Toxicology. 2018;120:196-212
  2. 2. Patel SP, Vasavda C, Ho B, Meixiong J, Dong X, Kwatra SG. Cholestatic pruritus: Emerging mechanisms and therapeutics. Journal of the American Academy of Dermatology. 2019
  3. 3. Miszczuk GS, Barosso IR, Larocca MC, Marrone J, Marinelli RA, Boaglio AC, et al. Mechanisms of canalicular transporter endocytosis in the cholestatic rat liver. Biochimica et Biophysica Acta - Molecular Basis of Disease. 2018;1864:1072-1085
  4. 4. Roma MG, Barosso IR, Miszczuk G, Crocenzi FA, Pozzi EJS. Dynamic localization of hepatocellular transporters: Role in biliary excretion and impairment in cholestasis. Current Medicinal Chemistry. 2019;26:1113-1154
  5. 5. Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S. The current state of serum biomarkers of hepatotoxicity. Toxicology. 2008;245:194-205
  6. 6. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: A guide for clinicians. CMAJ. 2005;72:367-379
  7. 7. EASL. European Association for the Study of the liver EASL clinical practice guidelines: Management of cholestatic liver diseases. Journal of Hepatology. 2009:237-267
  8. 8. Navarro VJ, Senior JR. Drug-related hepatotoxicity. The New England Journal of Medicine. 2006;354:731-739
  9. 9. Düll MM, Kremer AE. Treatment of pruritus secondary to liver disease. Current Gastroenterology Reports. 2019;21(9):48
  10. 10. Roda A, Gioacchini AM, Manetta AC, Cerrè C, Montagnani M, Fini A. Bile acids: Physico-chemical properties, function and activity. Journal of Gastroenterology. 1995;27:327-331
  11. 11. Lucangioli S, Carducci C, Tripodi V, Kenndler E. Retention of bile salts in micellar electrokinetic chromatography: Relation of capacity factor to octanol–water partition coefficient and critical micellar concentration. Journal of Chromatography B. 2001;765:113-120
  12. 12. Hoffman A, Roda A. Physicochemical properties of bile acids and their relationshiio to biological properties: An overview of the problem. Journal of Lipid Research. 1984;25:1477-1488
  13. 13. Stales B, Fonseca V. Bile acids and metabolic regulation: Mechanisms and clinical responses to bile acid sequestration. Diabetes Care. 2009;32(2):S237-S245
  14. 14. Tonin F, Arends IWCE. Latest development in the synthesis of ursodeoxycholic acid (UDCA): A critical review. Beilstein Journal of Organic Chemistry. 2018;14:470-483
  15. 15. Tripodi V, Lucangioli S, Scioscia S, Carducci C. Simultaneous determination of free and conjugated bile acids in serum by cyclodextrin-modified micellar electrokinetic chromatography. Journal of Chromatography B. 2003;785:147-155
  16. 16. Balistreri W. Fetal and neonatal bile aids synthesis and metabolism-clinical implications. Journal of Inherited Metabolic Disease. 1991;14:459-477
  17. 17. Hofmann A. Targeting drugs to the enterohepatic circulation: Lessons from bile acids and other endobiotics. Journal of Controlled Release. 1985;2:3-11
  18. 18. Hofmann A. Pharmacology of ursodeoxycholic acid, and enterohepatic drug. Scandinavian Journal of Gastroenterology. 1994;29:S1-S15
  19. 19. Aldini R, Montiagnani M, Roda A, Hrelia S, Biagi P, Roda E. Intestinal absorption of bile acid in the rabbit: Different transport rates in jejunum and ileum. Gastroenterology. 1996;110:458-459
  20. 20. Bouscarel B, Nussbaum R, Dubner H, Fromm H. The roll of sodium in uptake of ursodeoxycholic acid in isolated hamster hepatocytes. Hepatology. 1995;21:145-154
  21. 21. Cohen B, Hofmann A, Mosbach E. Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit. Gastroenterology. 1986;91:189-197
  22. 22. Palmer R. Bile acid, liver injury, and liver disease. Archives of Internal Medicine. 1972;130:606-617
  23. 23. Mitsuyoshi H, Nakashima T, Sumida Y, Yoh T, Nakajima Y, Ishikawa H, et al. Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants. Biochemical and Biophysical Research Communications. 1999;263:537-542
  24. 24. Arisawa S, Ishida K, Kameyama N, Ueyama J, Hattori A, Tatsumi Y, et al. Ursodeoxycholic acid induces glutathione synthesis through activation of PI3K/Akt pathway in HepG2 cells. Biochemical Pharmacology. 2009;77:858-866
  25. 25. Kang S, Song J, Kang H, Kim S, Lee Y, Park D. Insulin can block apotosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells. European Journal of Endocrinology. 2003;148:147-155
  26. 26. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochimica et Biophysica Acta. 2004;1660(1-2):171-199
  27. 27. Quinzii C, Hirano M. Coenzyme Q and mitochondrial disease. Developmental Disabilities Research Reviews. 2010;16(2):183-188
  28. 28. Sun IL, Sun EE, Crane FL, Morré DJ, Lindgren A, Löw H. Requirement for coenzyme Q in plasma membrane electron transport. Proceedings of the National Academy of Sciences of the United States of America. 1992;89:11126-11130
  29. 29. Gille L, Nohl H. The existence of a lysosomal redox chain and the role of ubiquinone. Archives of Biochemistry and Biophysics. 2000;375:347-354
  30. 30. Fontaine E, Ichas F, Bernardi P. A ubiquinone-binding site regulates the mitochondrial permeability transition pore. The Journal of Biological Chemistry. 1998;273:25734-25740
  31. 31. Walter L, Miyoshi H, Leverve X, Bernard P, Fontaine E. Regulation of the mitochondrial permeability transition pore by ubiquinone analogs. A progress report. Free Radical Research. 2002;36:405-412
  32. 32. Echtay KS, Winkler E, Klingenberg M. Coenzyme Q is an obligatory cofactor for uncoupling protein function. Nature. 2000;408:609-613
  33. 33. Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R. The mitochondrial medicine society. A modern approach to the treatment of mitochondrial disease. Current Treatment Options in Neurology. 2009;11(6):414-430
  34. 34. Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, et al. COQ2 nephropathy: A newly described inherited mitochondriopathy with primary renal involvement. Journal of the American Society of Nephrology. 2007;18:2773-2780
  35. 35. Duncan AJ, Bitner-Glindzicz M, Meunier B, Costello H, Hargreaves IP, López LC, et al. A nonsense mutation in COQ9 causes autosomalrecessive neonatal-onset primary coenzyme Q10 deficiency: A potentially treatable form of mitochondrial disease. American Journal of Human Genetics. 2009;84:558-566
  36. 36. Lagier-Tourenne C, Tazir M, Lopez LC, Quinzii CM, Assoum M, Drouot N, et al. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. American Journal of Human Genetics. 2008;82:661-672
  37. 37. Lopez LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ, Naini A, et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. American Journal of Human Genetics. 2006;79:1125-1129
  38. 38. Mollet J, Delahodde A, Serre V, Chretien D, Schlemmer D, Lombes A, et al. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. American Journal of Human Genetics. 2008;82:623-630
  39. 39. Mollet J, Giurgea I, Schlemmer D, Dallner G, Chretien D, Delahodde A, et al. Pre-nyldiphosphate synthase, subunit 1 (PDSS1) and OHbenzoate polyprenyltransferase (COQ2) mutations in ubiquinone deficiency and oxidative phosphorylation disorders. The Journal of Clinical Investigation. 2007;117:765-772
  40. 40. Quinzii C, Naini A, Salviati L, Trevisson E, Navas P, Dimauro S, et al. A mutation in Para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. American Journal of Human Genetics. 2006;78:345-349
  41. 41. Desbats MA, Lunardi G, Doimo M, Trevisson E, Salviati L. Genetic bases and clinical manifestations of coenzyme Q10 (CoQ 10) deficiency. Journal of Inherited Metabolic Disease. 2015;38(1):145-156
  42. 42. Quinzii CM, López LC, Naini A, DiMauro S, Hirano M. Human CoQ10 deficiencies. BioFactors. 2008;32:113-118
  43. 43. Cobanoglu U, Demir H, Cebi A, Sayir F, Alp HH, Akan Z, et al. Lipid peroxidation, DNA damage and coenzyme Q10 in lung cancer patients– Markers for risk assessment? Asian Pacific Journal of Cancer Prevention. 2011;12:1399-1403
  44. 44. Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich’s ataxia: Predictor of efficacy of vitamin E and coenzyme Q10 therapy. European Journal of Neurology. 2008;15:1371-1379
  45. 45. Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: An update. Nutrition. 2010;26:250-254
  46. 46. Molineux S, Young J, Florkowshi C, Lever M. Coenzyme Q10: Is there a clinical role and a case for measurement? Clinical Biochemist Reviews. 2008;29:71-78
  47. 47. Yubero D, Montero R, Martín MA, et al. Secondary coenzyme Q10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders. Mitochondrion. 2016;30:51-58
  48. 48. Compagnoni G, Lista G, Giuffre B, Mosca F, Marini A. Coenzyme Q10 levels in maternal plasma and cord blood: Correlations with mode of delivery. Biology of the Neonate. 2004;86:104-107
  49. 49. Martinefski MR, Contin MD, Rodriguez MR, Geréz EM, Galleano ML, Lucangioli SE, et al. Coenzyme Q in pregnant women and rats with intrahepatic cholestasis. Liver International. 2014;34(7):1040-1048
  50. 50. Martinefski MR, Cocucci SE, Di Carlo MB, Vega HR, Lucangioli SE, Perazzi BE, et al. Fetal coenzyme Q10 deficiency in intrahepatic cholestasis of pregnancy. Clinics and Research in Hepatology and Gastroenterology. 2019;S2210-7401(19):30171-30178
  51. 51. Perez MJ, Velasco E, Monte MJ, Gonzalez-Buitrago JM, Marin JJ. Maternal ethanol consumption during pregnancy enhances bile acidinduced oxidative stress and apoptosis in fetal rat liver. Toxicology. 2006a;225:183-194
  52. 52. Perez MJ, Macias RI, Duran C, Monte MJ, Gonzalez-Buitrago JM, Marin JJ. Oxidative stress and apoptosis in fetal rat liver induced by maternal cholestasis. Protective effect of ursodeoxycholic acid. Journal of Hepatology. 2005;43:324-332
  53. 53. Perez MJ, Macias RI, Marin J. Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta. 2006b;27:34-41
  54. 54. Stocker R, Bowry VW. Frei B Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(5):1646-1650
  55. 55. Parola M, Leonarduzzi G, Robino G, Albano E, Poli G, Dianzani MU. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis. Free Radical Biology & Medicine. 1996;20(3):351-359
  56. 56. Singh S, Shackleton G, Ah-Sing E, Chakraborty J, Bailey ME. Antioxidant defenses in the bile duct-ligated rat. Gastroenterology. 1992;103(5):1625-1629
  57. 57. Sokol RJ, Devereaux M, Khandwala RA. Effect of dietary lipid and vitamin E on mitochondrial lipid peroxidation and hepatic injury in the bile duct-ligated rat. Journal of Lipid Research. 1991;32(8):1349-1357
  58. 58. Sokol RJ, Winklhofer-Roob BM, Devereaux MW, McKim JM Jr. Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids. Gastroenterology. 1995;109(4):1249-1256
  59. 59. Aboutwerat A, Pemberton PW, Smith A, Burrows PC, McMahon RF, Jain SK, et al. Oxidant stress is a significant feature of primary biliary cirrhosis. Biochimica et Biophysica Acta. 2003;1637(2):142-150
  60. 60. Sokol RJ, Dahl R, Devereaux MW, Yerushalmi B, Kobak GE, Gumpricht E. Human hepatic mitochondria generate reactive oxygen species and undergo the permeability transition in response to hydrophobic bile acids. Journal of Pediatric Gastroenterology and Nutrition. 2005;41(2):235-243
  61. 61. Vendemiale G, Grattagliano I, Lupo L, Memeo V, Altomare E. Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage. Journal of Hepatology. 2002;37(5):601-605
  62. 62. Krähenbühl S, Talos C, Fischer S, Reichen J. Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria. Hepatology. 1994;19(2):471-479
  63. 63. Yerushalmi B, Dahl R, Devereaux MW, Gumpricht E, Sokol RJ. Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology. 2001;33(3):616-626
  64. 64. Botla R, Spivey JR, Aguilar H, Bronk SF, Gores GJ. Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: A mechanism of UDCA cytoprotection. The Journal of Pharmacology and Experimental Therapeutics. 1995;272(2):930-938
  65. 65. Dueland S, Reichen J, Everson GT, Davis R. Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats. The Biochemical Journal. 1991;280(Pt 2):373-377
  66. 66. Erickson SK, Jaeckle S, Lear SR, Brady SM, Havel RJ. Regulation of hepatic cholesterol and lipoprotein metabolism in ethinyl estradiol-treated rats. Journal of Lipid Research. 1989;30(11):1763-1771
  67. 67. Heuman DM, Hernandez CR, Hylemon PB, Kubaska WM, Hartman C, Vlahcevic ZR. Regulation of bile acid synthesis. I. Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat. Hepatology. 1988;8(2):358-365
  68. 68. Shefer S, Nguyen L, Salen G, Batta AK, Brooker D, Zaki FG, et al. Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate. The Journal of Clinical Investigation. 1990;85(4):1191-1198
  69. 69. Davis JM, Auten RL. Maturation of the antioxidant system and the effects on preterm birth. Seminars in Fetal & Neonatal Medicine. 2010;15(4):191-195
  70. 70. Colombo C, Roda A, Roda E, Buscaglia M, dell’gnola CA, Filippetti P, et al. Correlation between fetal and maternal serum bile acid concentrations. Pediatric Research. 1985;19(2):227-231
  71. 71. Geenes V, Lövgren-Sandblom A, Benthin L, Lawrance D, Chambers J, Gurung V, et al. The reversed feto-maternal bile acid gradient in intrahepatic cholestasis of pregnancy is corrected by ursodeoxycholic acid. PLoS One. 2014;9(1):e83828
  72. 72. Yubero D, Montero R, Armstrong J, Espinós C, Palau F, Santos-Ocaña C, et al. Molecular diagnosis of coenzyme Q10 deficiency. Expert Review of Molecular Diagnostics. 2015;15(8):1049-1059

Written By

Manuela R. Martinefski, Silvia E. Lucangioli, Liliana G. Bianciotti and Valeria P. Tripodi

Submitted: June 25th, 2019 Reviewed: December 11th, 2019 Published: December 30th, 2019