Frontiers in Bioactive Compounds: At the Crossroads between Nutrition and Pharmacology

M. Victorina Aguilar, Cristina Otero, M. Victorina Aguilar, Cristina Otero

• Publisher: Bentham Science Publishers
• Year: 2017
• Print ISBN:
  9781681084305
• eBook ISBN:
  9781681084299
• Topic: Medicine
• Subtopic: Pharmacology

This volume presents different aspects related to bioactive compounds, starting with their natural state in raw sources, physicochemical characterization and employment in pharmacy and medicine. The volume is divided into three parts. The first part describes the chemicals structure of bioactive compounds from different natural sources such as olive oils, wines, and medicinal plants. Special attention has been given to identifying the bioactive composition within variations of these natural sources (for example, extra virgin, ordinary or lampante olive oils). The second part of the volume presents the principal methods used for detecting, identifying and quantifying bioactive compounds. Emphasis is given to the use of different types of sensors or biosensors, and multisensor systems in combination with analytical techniques. The final part explains the principal methods for protection of bioactive compounds and the implication of bioactive compounds in pharmacy. This volume is a useful guide for novice researchers interested in learning research methods to study bioactive compounds.

Urso-, Glycoursodeoxycholic and Tauroursodeoxycholic Acids: From Basic Research to Clinical Applications in CNS Disorders

INTRODUCTION

Bile acids (BAs) are physiological detergents that derive from cholesterol (Fig. 1) and are synthesized in human liver at a rate of 0.2-0.6 g per day (averaging 0.5 g). BAs are implicated in generating bile flow to facilitate intestinal absorption and transport of nutrients, fats and vitamins [1]. Once BA biosynthesis is completed, with the generation of the primary BAs, cholic acid (CA, 3α,7α,12α-trihydroxy- 5β-cholan-24-oic acid) and chenodeoxycholic acid (CDCA, 3α,7α-dihydroxy- 5β-cholan-24-oic acid), there is conjugation with the amino acids taurine (tauroconjugates) and glycine (glycoconjugates) in the liver. The BAs are then excreted into the bile canaliculi through the canalicular protein bile-salt export pump (BSEP) [2, 3] (First metabolic pump system, step 1 in Fig. (2)). Bile enters the gallbladder where it is concentrated and stored, before its release into the intestine after meals, to participate in fat digestion and absorption (reviewed in [4]). The bacterial flora converts the primary BAs into the secondary BAs deoxycholic acid (DCA) from CA, and lithocholic acid (LCA) from CDCA, by the action of the enzyme 7-α-dehydroxylase. These BAs are efficiently reabsorbed entering in the enterohepatic circulation (Second metabolic pump system, step 2 in Fig. (2)) and being transported to the liver (step 3) by portal blood, where they join the primary BAs, before being conjugated and re-excreted into the bile [5]. This recycling is known as the enterohepatic circulation of BAs and can occur several times per day [3]. In addition, BAs that arrive into the colon can be deconjugated by bacterial enzymes and originate the free BAs species that are excreted in the faeces (5% of total BAs).

In humans, the bile acid pool is formed by the primary and secondary BAs. In human serum, the total BA concentration is usually between 2 and 10 μmol/L [6 - 8] and bile representation of CA, CDCA and DCA is approximately 40:40:20, respectively [5]. However, there are variations by ageing since the BA synthesis and bile flow decreases markedly in the elderly [8].

Fig. (1))
Chemical structures of the primary bile acids (cholic and chenodeoxycholic acids) synthesized from the cholesterol in the liver. The formation of ursodeoxycholic acid, the 7 beta-hydroxy epimer of chenodeoxycholic acid, is produced in the colon by bacterial transformation. The conjugation of bile acids with glycine and taurine occurs in the liver, as the formation of glycoursodeoxycholic acid and tauroursodeoxycholic acid from the ursodeoxycholic acid.

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. One of the most used drugs in the treatment of cholestasis is the ursodeoxycholic acid (UDCA), with the systematic (IUPAC) name of 3α,7β-dihydroxy-5β-cholan-24-oic acid (Fig. 1). It is a secondary BA with hydrophilic properties, formed by 7β-epimerization of the CDCA in the gut by intestinal bacteria [9]. UDCA exists in low quantity in human bile (about 3% of the bile acid pool) [10], but in high amount in the Chinese black bear [11]. It has been used for many centuries by the Chinese traditional medicine in the treatment of biliary stone disease [12]. Today, instead of being obtained from the bile of the black bear, UDCA is synthesized from CA by several manufacturers and marketed as Ursodiol, Ursofalk and Destolit, among other designations.

Fig. (2))
Synthesis and enterohepatic circulation of bile acids (BAs). Secreted BAs by the liver consist of 95% old and recycled species and 5% (0.5 g) newly synthesized BAs. Conjugated BAs are secreted into bile and stored in the gallbladder under high concentration achieved by the elimination of water and electrolytes. Transport across the canalicular membrane of the liver is an ATP-dependent process assisted by the bile-salt excretion pump (BSEP) protein expression (first metabolic pump system, step 1). After each meal, gallbladder contraction empties BAs into the intestinal tract. When in the intestinal tract, BAs can be absorbed in the upper intestine by passive diffusion, but most of them (95%) are absorbed in the ileum by an active Na+-dependent transport system (second metabolic pump, step 2) and excreted into portal blood circulation (Portal vein) back to the sinusoid of hepatocytes. BAs are actively transported into hepatocytes mainly by sodium (Na⁺)-taurocholate cotransporting polypeptide (NTCP) (step 3). BAs are recycled 3-15 times a day and the amount that is lost in the faeces (0.5 g/day) is reloaded by de novo synthesis in the liver to maintain a constant BA pool of about 3 g.

After oral administration, the free species UDCA is subsequently absorbed in the small bowel enters the portal vein and undergoes efficient extraction from portal blood by the healthy liver, where it is conjugated to originate taurourso-deoxycholic acid (TUDCA) and mostly glycoursodeoxycholic acid (GUDCA) (Fig. 1), which should be then considered as the species having the highest clinical relevance in people taking oral UDCA [13].

Intriguingly, the majority of publications mainly deal with UDCA and TUDCA species and the information on the mechanisms of action of GUDCA and its role during the therapy with UDCA or TUDCA is almost inexistent. Indeed, while TUDCA has been provided as Taurolite by an Italian company with the recommended dose of 7–15 mg/kg body weight daily [14], GUDCA is not commercialized.

This review presents evidence that GUDCA is the main species formed after therapy with UDCA and that many of the benefits usually attributed to the UDCA therapy should be understood as being derived from the elevated levels of GUDCA in circulation and p...

Table of contents

• Welcome
• Table OF Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE I
• PREFACE II
• List of Contributors
• From Pharma to Food: Mechanistic Target Identification for Bioactive Compounds Using Nutritional Systems Biology
• Advances in the Determination of Bioactive Peptides in Foods
• Overview of In vivo and In vitro Methods for Assessing Bioavailability of Bioactive Food Compounds
• Novel Nutrigenomics Avenues in Nutraceuticals Use: The Current Status of Fermented Papaya Preparation
• Bioactive Properties of Sugar Fatty Acid Esters
• Arabinoxylans: Bioactivities in Relation to Their Molecular Structure
• Yam (Dioscorea species): Future Functional Wild Food of Tribal Odisha, India
• Biological and Medical Effects of Saponins of Hedera helix and Other Medicinal Plants
• Bioactive Compounds and Diabetes
• Evidence to the Vitamin E and Other Antioxidants Influencing Cardiovascular Diseases
• Metabolic Syndrome and Bioactive Compounds
• Urso-, Glycoursodeoxycholic and Tauroursodeoxycholic Acids: From Basic Research to Clinical Applications in CNS Disorders
• Bioactive Compounds and Prostate Cancer Therapy
• Health Effects and Risks of Caffeine, Theobromine and Theophylline
• Effect of Cooking on the Bioactive Compounds