By E. Tufail. Irvine University College of Law.

CHAPTER 34 / CHOLESTEROL ABSORPTION fosamax 35mg fast delivery, SYNTHESIS 70 mg fosamax free shipping, METABOLISM buy generic fosamax 35mg line, AND FATE 631 action (Fig cheap fosamax 70mg. Lithocholic acid order fosamax 70 mg on-line, a secondary bile salt that has a hydroxyl group Primary bile salts only at position 3, is the least soluble bile salt. The second- OH CH3 ary bile salts may be reconjugated in the liver, but they are not rehydroxylated. The 12 bile salts are recycled by the liver, which secretes them into the bile. This entero- CH3 hepatic recirculation of bile salts is extremely efficient. Less than 5% of the bile salts entering the gut are excreted in the feces each day. Because the steroid nucleus 3 7 cannot be degraded in the body, the excretion of bile salts serves as a major route for removal of the steroid nucleus and, thus, of cholesterol from the body. TRANSPORT OF CHOLESTEROL BY THE BLOOD – LIPOPROTEINS COO Because they are hydrophobic and essentially insoluble in the water of the blood, CH3 cholesterol and cholesterol esters, like triacylglycerols and phospholipids, must be 12 transported through the bloodstream packaged as lipoproteins. Each lipoprotein particle is composed of a core of hydropho- bic lipids such as cholesterol esters and triacylglycerols surrounded by a shell of 3 7 polar lipids (the phospholipids), which allows a hydration shell to form around the HO OH lipoprotein (see Fig. This occurs when the positive charge of the nitrogen atom Chenocholic acid of the phospholipid (phosphatidylcholine, phosphatidylethanolamine, or phos- phatidylserine) forms an ionic bond with the negatively charged hydroxyl ion of the environment. In addition, the shell contains a variety of apoproteins that also increase the water solubility of the lipoprotein. Free cholesterol molecules are dispersed Secondary bile salts throughout the lipoprotein shell to stabilize it in a way that allows it to maintain its – COO spherical shape. The major carriers of lipids are chylomicrons (see Chapter 32), OH VLDL, and HDL. Metabolism of CH3 chylomicrons leads to chylomicron remnant formation. The apoproteins 3 7 (“apo” describes the protein within the shell of the particle in its lipid-free form) not HO only add to the hydrophilicity and structural stability of the particle but have other Deoxycholic acid functions as well: (1) they activate certain enzymes required for normal lipoprotein metabolism and (2) they act as ligands on the surface of the lipoprotein that target specific receptors on peripheral tissues that require lipoprotein delivery for their COO– innate cellular function. Their tissue source, molecu- CH3 12 lar mass, distribution within lipoproteins, and metabolic functions are shown in Table 34. CH3 The lipoproteins themselves are distributed among eight major classes. Some of their characteristics are shown in Table 34. Each class of lipoprotein has a specific 3 7 function determined by its apolipoprotein content, its tissue of origin, and the pro- HO portion of the macromolecule made up of triacylglycerols, cholesterol esters, free Lithocholic acid cholesterol, and phospholipids (see Tables 34. Structures of the primary and sec- ondary bile salts. The Chylomicrons jugates with taurine or glycine in the liver. After secretion into the intestine, they may be Chylomicrons are the largest of the lipoproteins and the least dense because of their deconjugated and dehydroxylated by the bac- rich triacylglycerol content. They are synthesized from dietary lipids (the “exoge- terial flora, forming secondary bile salts. Note nous” lipoprotein pathway) within the epithelial cells of the small intestine and then that dehydroxylation occurs at position 7, secreted into the lymphatic vessels draining the gut (see Fig. They enter the forming the deoxy family of bile salts. The major apoproteins of chylomicrons are apoB-48, apoCII, and apoE (see Table 34. The apoCII activates lipoprotein lipase 632 SECTION SIX / LIPID METABOLISM Table 34. CHARACTERISTICS OF THE MAJOR APOPROTEINS Primary Tissue Molecular Mass Lipoprotein Apoprotein Source (Daltons) Distribution Metabolic Function ApoA-1 Intestine, liver 28,016 HDL (chylomicrons) Activates LCAT; structural component of HDL ApoA-II Liver 17,414 HDL (chylomicrons) Unknown ApoA-IV Intestine 46,465 HDL (chylomicrons) Unknown (may facilitate transport of other apoproteins between HDL and chylomicrons) ApoB-48 Intestine 264,000 Chylomicrons Assembly and secretion of chylomicrons from small bowel ApoB-100 Liver 540,000 VLDL, IDL, LDL VLDL assembly and secretion structured protein of VLDL, IDL, and LDL ligand for LDL receptor ApoC-1 Liver 6,630 Chylomicrons, Unknown; may inhibit hepatic uptake of VLDL, IDL, HDL chylomicron and VLDL remnants ApoC-II Liver 8,900 Chylomicrons, Cofactor activator of lipoprotein lipase (LPL) VLDL, IDL, HDL ApoC-III Liver 8,800 Chylomicrons, Inhibitor of LPL; may inhibit hepatic uptake of VLDL, IDL, HDL chylomicrons and VLDL remnants ApoE Liver 34,145 Chylomicron Ligand for binding of several lipoproteins to the remnants, VLDL, LDL receptor, to the LDL receptor-related IDL, HDL protein (LRP) and possibly to a separate apo-E receptor. Apo(a) Liver Lipoprotein Unknown “little” a (Lp(a)) (LPL), an enzyme that projects into the lumen of capillaries in adipose tissue, cardiac muscle, skeletal muscle, and the acinar cells of mammary tissue.

Reactive Oxygen Species (ROS) and Reactive Nitrogen–Oxygen Species (RNOS) Reactive Species Properties O2 Produced by the electron transport chain and at other sites buy 35 mg fosamax free shipping. H O Not a free radical discount 70mg fosamax amex, but can generate free radicals by reaction with a transition metal (e order 35 mg fosamax amex. Can diffuse 2 2 Hydrogen peroxide into and through cell membranes order 70 mg fosamax otc. OH• The most reactive species in attacking biologic molecules discount fosamax 70mg line. Produced from H2O2 in the Fenton reaction in the Hydroxyl radical presence of Fe2 or Cu. RO• , R•, R-S•· Organic free radicals (R denotes remainder of the compound. RCOO•· An organic peroxyl radical, such as occurs during lipid degradation (also denoted LOO•) Peroxyl radical HOCl Produced in neutrophils during the respiratory burst to destroy invading organisms. Toxicity is through Hypochlorous acid halogenation and oxidation reactions. Attacking species is OCl O Tc Oxygen with antiparallel spins. Produced at high oxygen tensions from absorption of uv light. Decays so fast 2 Singlet oxygen that it is probably not a significant in vivo source of toxicity. A free radical produced endogenously by nitric oxide synthase. Combines with O2 Nitric oxide or other oxygen-containing radicals to produce additional RNOS. A strong oxidizing agent that is not a free radical. It can generate NO (nitrogen dioxide), which 2 Peroxynitrite is a radical. Because hydrogen peroxide is lipid soluble, it can diffuse through membranes and generate OH• at localized Fe2 - or Cu -containing sites, such as the mitochondria. Hydrogen peroxide is also the precursor of hypochlorous acid (HOCl), a powerful oxidizing agent that is produced endogenously and enzymatically by phagocytic The Haber–Weiss reaction cells. Organic peroxy radicals are Superoxide Hydrogen intermediates of chain reactions, such as lipid peroxidation. Other organic radicals, peroxide such as the ethoxy radical, are intermediates of enzymatic reactions that escape into H+ solution (see Table 24. An additional group of oxygen-containing radicals, termed RNOS, contain nitro- gen as well as oxygen. These are derived principally from the free radical nitric O2 H2O •OH oxide (NO), which is produced endogenously by the enzyme nitric oxide synthase. Oxygen Water Hydroxyl Nitric oxide combines with O2 or superoxide to produce additional RNOS. Major Sources of Primary Reactive Oxygen Species in the Cell H2O2 ROS are constantly being formed in the cell; approximately 3 to 5% of the oxy- Hydrogen gen we consume is converted to oxygen free radicals. Some are produced as acci- peroxide 2+ dental by-products of normal enzymatic reactions that escape from the active site Fe of metal-containing enzymes during oxidation reactions. Others, such as hydro- Fe3+ gen peroxide, are physiologic products of oxidases in peroxisomes. Deliberate – production of toxic free radicals occurs in the inflammatory response. Drugs, •OH + OH natural radiation, air pollutants, and other chemicals also can increase formation Hydroxyl Hydroxyl of free radicals in cells. CoQ GENERATES SUPEROXIDE by the nonenzymatic Haber–Weiss and Fenton One of the major sites of superoxide generation is Coenzyme Q (CoQ) in the mito- reactions. In the simplified versions of these chondrial electron transport chain (Fig. The one-electron reduced form of reactions shown here, the transfer of single electrons generates the hydroxyl radical. ROS CoQ (CoQH•) is free within the membrane and can accidentally transfer an electron are shown in blue. In addition to Fe2 ,Cu and to dissolved O2, thereby forming superoxide. In contrast, when O2 binds to many other metals can also serve as single- cytochrome oxidase and accepts electrons, none of the O2 radical intermediates are electron donors in the Fenton reaction.

Some investigators suggested that survival approached normal purchase fosamax 70mg with visa, while others indicated that the effect was only seen early in therapy and then disappeared order fosamax 35 mg on line. However buy fosamax 70 mg on line, many of the studies have been criticized due to methodological flaws purchase 70mg fosamax with mastercard, problems with patient selection generic 70 mg fosamax, and possible biases. One study of particular interest (83) utilized a population-based study design (retrospective) to avoid many of these flaws and examine the change in survival related to LD therapy. The study included patients treated from 1964 to 1978 to include patients treated early and late as well as untreated cases. Results indicated that survival for all patients was significantly poorer than that of the general population but was better in treated than in untreated PD. Throughout the entire 17 years of follow-up there was reduced risk of death with LD therapy. One other area of interest relates to the timing of LD therapy. Does early or later intervention affect the survival rates? They divided patients into three groups: group one, 1–3 years of PD; group two, 4–6 years of PD; group three, 7–9 years of PD. They used observed-to-expected death rate (from a group of similar make-up in the general population) ratios as measures of survival. When duration of therapy is held constant at 15 years, the ratio was higher for patients with longer duration of disease. When duration of disease was held constant at 17 years, the patients in group one had a better mortality ratio than the other two groups. Thus, early initiation of LD therapy was beneficial to life expectancy. They suggested that the improved survival related to the symptomatic effect of the drug, keeping patients more active in the earlier years. Of those, 98 were treated for 2 or more years while 47 were treated for <2 years. However, there were biases that led to an underestimation of mortality in the delayed treatment group, including 47 patients who were lost to follow-up. They concluded that survival from early LD initiation is the same or better than late. IS THERE AN ASSOCIATION BETWEEN LD THERAPY AND MELANOMA? Previous reports as well as the Physician’s Desk Reference caution against the use of LD in PD patients with a history of melanoma. As recently as 1998, Pfutzner and Przybilla reported that while no causal relationship has been proven, patients with a history of malignant melanoma receiving LD therapy should be carefully followed for the development of new pigmented lesions (86). Anecdotal reports exist in the literature of the potential carcinogenic effects of LD therapy and its potential to activate malignant melanoma (87). Because dopamine acts on and is produced by pigmented neurons, it has been proposed that levodopa may affect the activity of melanocytes, possibly promoting malignant transformation. They reported on nine patients with PD and a history of melanoma who were treated with LD, none of whom had a recurrence. They concluded that LD therapy could be used safely in PD patients with melanoma. Woofter and Manyam (87) reported on a 74-year-old man with PD who was treated with LD and whose malignant melanoma was later discovered. Prior to the diagnosis of melanoma, it was estimated that the patient received 5. The patient continued with LD treatment for more than 10 years, with an additional 4. They concluded that withholding LD therapy for fear of accelerating melanoma was unwarranted (87). Thus, despite the continued warning appearing in the prescribing literature for LD, there appears to be no causal relationship between LD therapy in PD and the occurrence of malignant melanoma. A history of melanoma in a PD patient should not prohibit the use of LD. LEVODOPA CHALLENGE TEST It can be difficult to accurately differentiate PD from other forms of parkinsonism, especially during early presentation. LD administration can be used for diagnostic purposes as PD patients respond more frequently and robustly to LD compared with other forms of parkinsonism. Clarke and Davies recently published a review of 13 studies that examined whether an acute LD or apomorphine challenge test could aid in Copyright 2003 by Marcel Dekker, Inc.

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