Bile acid biosynthesis intermediates

It is impossible to determine the relative contributions of each of these pathways to total bile-acid biosynthesis, due to the nature of the data. Some values were obtained from patients whose gallbladders had been surgically removed other patients would be atypical due to illness, and many data were obtained from experimental animals, which may metabolise these compounds differently from humans. Also, the exact order of many of the reactions is not known, since the intermediates may act as substrates for more than one enzyme. Further details for these reactions can be found in reviews by Chiang, Moore et al. and Fuchs et al ... 

The exact contributions of these alternate pathways to total hepatic bile acid synthesis in normal subjects is not certain, although 26-hydroxylation is usually regarded as the major pathway. In addition, it should be pointed out that current views of hepatic cholic acid and chenodeoxycholic acid synthesis are based primarily oh studies carried out in the rat. More recent studies, which have involved the administration of labeled bile acid intermediates to patients, have suggested that bile acid biosynthesis is more complex than previously thought and that multiple pathways exist to convert cholesterol to bile acids (Vll). 

Shefer, S., Salen, G., Gheng, F. W., Dayal, B., Batta, A. K., Tint, G. S., Bose, A. K., and Pramanik, B. N., Ghemical ionisation-mass spectrometric approach to structure determination of an intermediate in bile acid biosynthesis. Anal. Biochem. 121, 23-30... 

The possibUity of multiple pathways in bile acid biosynthesis in man has been discussed by Vlahcevic et al. [180-182]. A number of labelled 7 -hydroxylated intermediates in bile acid biosynthesis were administered to bile fistula patients as well as patients with an intact enterohepatic circulation. In accordance with previous work with bile fistula rats, the spedfic activity of the isolated chohc add was in general considerably lower than that of chenodeoxychohc acid. On the basis of this finding, it was suggested that a portion of chohc acid was synthesized via a route not involving initial 7a-hydroxylation of cholesterol. It must then be assumed that the administered intermediate mixes with the endogenous pool of the same steroid. However, due to compartmentation, the metabolic fate of a precursor reaching the hepatocyte might be different from that of the the same compound formed within the cell. Normally, the different precursors are present in the cells in trace amounts... 

The natural distribution and the chemical structure of bile alcohols and primitive bile acids indicate that these compounds found in lower vertebrates are evolutionary precursors of the common bile acids found in mammalian species. Haslewood proposed that the mechanism of conversion of cholesterol to the common bile acids in mammals is a recapitulation of the evolution of bile salts and thus would entail the intermediary formation of bile alcohols and primitive bile adds similar to or the same as those found in lower species [120]. Thus, studies have been carried out to test whether the naturally occurring bile alcohols and primitive bile acids are intermediates in the biosynthetic pathway between cholesterol and the C24 bile acids in mammals. There is no doubt that such studies contributed to the elucidation of the sequence of reactions in the biosynthesis of the mammalian C24 bile acids. 

Bile acid intermediates Disorders of bile acid biosynthesis, peroxisomal disorders Plasma, urine GC-MS, LC-MS/MS [26]... 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

In 1972, large amounts of THCA were firund in the bile of two unrelated young children with intrahepatic bile duct abnormalities (E5), suggesting a block in the biosynthesis of cholic acid. Tliree years later, this bile acid intermediate was also found in the bile, serum, and urine of a brother and sister with a similar paucity of intrahepatic bile ducts and cholestatic liver disease, which proved fotal (H3). DHCA or varanic acid could not be detected in these patients, so that the metabolic defect in this condition appeared to be specific for the enzyme involved in the conversion of THCA to varanic acid. Hanson et a/, speculated that THCA might have caused the... 

Hoshita et al. have shown that liver microsomes from the green iguana, in which the major biliary bile salt is tauroallocholate, convert 7a,12a-dihydroxycholest-4-en-3-one (XVII) into 5a-cholestane-3a,7a,12a-triol (XVIII) rather than into 5)8-choles-tane-3 ,7a,12a-triol (VIII) which is involved in cholic acid biosynthesis [164]. On the basis of this result and that obtained from studies with carp liver [151], it can be assumed that 5a-bile acids and alcohols are formed from cholesterol by a modification of the biosynthetic pathway to the corresponding 5y8 isomers in which the only difference is the stereospedfic saturation of the A double bond of the intermediate XVII. 

Figure 11-4. Abbreviated cholesterolbiosynthesis. Hydroxymethylglutary-Coenzyme-A reductase catalyzes the rate-limiting step in overall synthesis of cholesterol and is inhibited by it. This key intermediate is also utilized in biosynthesis of steroid horrmones, bile acids, and vitamins A, D. E, and K.

The Opening of Squalene-2,3-Epoxide Steroids are tetracyclic compounds that serve a wide variety of biological functions, including hormones (sex hormones), emulsifiers (bile acids), and membrane components (cholesterol). The biosynthesis of steroids is believed to involve an acid-catalyzed opening of squalene-2,3-epoxide (Rgure 14-6). Squalene is a member of the class of natural products called terpenes (see Section 25-8). The enzyme squalene epoxidase oxidizes squalene to the epoxide, which opens and frams a carbocation that cyclizes under the control of another enzyme. The cyclized intermediate rearranges to lanosterol, which is converted to cholesterol and other steroids. 

Bile acid CoA esters are the intermediates in the oxidative shortening of the side chain of the C27-bile acids ((3-oxidation) in the biosynthesis of bile acids. Therefore, the blood levels of the bile acid CoA esters and C27-bile acids are good markers for the diagnosis of peroxisomal disorders, such as Zellweger syndrome. The development and clinical applications of the LC-ESl-MS methods for bile acid CoA esters and Cav-bile acids have been reported. 

Another acid-base reaction of 79 with water, which is in the cellular medium, generates 80, which regenerates 75 by loss of a carboxylate unit, RC02. Note that both 77 and 80 are known as tetrahedral intermediates, which will be important in Chapter 20. While the focus of the reaction is conversion of a cholesterol ester to cholesterol and regeneration of the carboxylate unit derived from 76, the reaction is driven by acid-base reactions that occur on the enzyme, cholesterol esterase. Cholesterol is a part of mammalian cell membranes and it is very important for membrane permeability and fluidity. Cholesterol is an important precursor for the biosynthesis of bile acids and some fat-soluble vitamins. 

Plants synthesise a number of steroid substances from cycloartenol, including 4,4-drmethylsterols, 4-methylsterols and demethylsterols. Cycloartenol is a precursor of many other steroids that are aglycons of saponins, of steroidal glycoalkaloids and of other compounds. Lanosterol in animals is a precursor for the biosynthesis of the most important zoosterol cholesterol (3-114). An intermediate in the biosynthesis of cholesterol is 7-dehydrocholesterol, which is a precursor of vitamin D3 (see Section 5.3.1). Cholesterol in the body is used for the biosynthesis of steroid hormones and bile acids (3-126). 

A probable intermediate in the biosynthesis of allocholic acid, 3a,7a, 12a trihydroxy-5a-cholestan-26-oic acid, has been found in the bile of the giant salamander (39). Amimoto (43) obtained allocholic acid and a second radioactive acidic metabolite from bile of the giant salamander after administration of 27-deoxy-5a-cyprinol (3a,7a, 2a, 26-tetrahydroxy-5a-cholestane). The unknown acid was esterified, reduced with LiAlH4, and the product identified as 27-deoxy-5a-cyprinol. Okuda et at. (44) isolated a few crystals (m.p. 227 °C) from the bile of iguana and obtained the same product on reduction of the ester with LiAlH4. 

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