Liver mechanism

Nicotinic acid decreases formation and secretion of VLDL by the liver (mechanism III in Fig. 23.2). This action appears secondary to its ability to inhibit fatty acid mobilization from adipose tissue. Circulating free fatty acids provide the main source of fatty acids for hepatic... 

Pheiffer, B.H. Zimmerman, S.B. Deoxyribonucleic acid kinase from nuclei of rat liver mechanism, reversal, and inhibitors of the reaction. Biochemistry, 18, 2960-2963 (1979)... 

Organs and tissues performing functions such as storage (e.g. adipose tissue), chemical processing (e.g. liver), mechanical work (e.g. muscle) and excretion (e.g. kidney) tend to have membranes in which the n-6 fatty acids... 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

A second problem concerns delimiting the mechanisms of action which should be included in the definition, to exclude effects which are a secondary consequence of overt toxicity in other body systems. For example, disruption to the endocrine system caused by general metabolic disturbance, such as in severe liver damage, should not be grounds for calling a chemical an ED. 

Decreased production of yolk protein resulting from inhibition of either ovarian or liver function presents the fish with a similar choice to that resulting from decreased food availability. It can produce the same number of smaller eggs, or a smaller number of eggs of normal size, but the mechanism by which that choice is made is unclear. Since the decreased nutrient content of small eggs will result in smaller larvae with a decreased survival rate, the net result in both cases may be a... 

Acute Liver Damage Several compounds (e.g., dimethyl iiitrosoamine, carbon tetrachloride, and thioacetamide) cause necrosis of hepatocytes by inhibiting pro tein syndiesis at the translational level, i.e., by inhibiting the addition of new amino adds into the protein chain being sjTithetized. This is not, however, the only mechanism. Ethioiiine is a compound which inhibits protein synthesis bur doe not induce... 

Accumulation of lipids in the liver (steatosis) is one possible mechanism for liver toxicity. Several compounds causing necrosis of hepatocytes also cause steatosis. There are, however, some doubts that steatosis would be the primary cause of liver injury. Several compounds cause steatosis (e.g., puro-mycin, cycloheximide) without causing liver injury. Most of the accumulated lipids are triglycerides. In steatosis, the balance between the synthesis and excretion of these lipids has been disturbed (see Table 5.13). 

The procedure for recalculating the HI by effect and by mechanism of action is briefly described later. If one of the effect-specific luizard indices exceeds unity, consideration of tlic mechanism of action might be warranted. A strong case is required, however, to indicate that two compounds which produce adverse effects on the same organ system (c.g., liver), altliough by different mechanisms, should not be treated as dose additive. Any such determination should be reviewed. 

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

Uptake of LCFAs across the lipid-bilayer of most mammalian cells occurs through both a passive diffusion of LCFAs and a protein-mediated LCFA uptake mechanism. At physiological LCFA concentrations (7.5 nM) the protein-mediated, saturable, substrate-specific, and hormonally regulated mechanism of fatty acids accounts for the majority (>90%) of fatty acid uptake by tissues with high LCFA metabolism and storage such as skeletal muscle, adipose tissue, liver,... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha (a), beta ((3), gamma (y) and delta (8), and four tocotrienols (also a, (3, y, and 8). a-Tocopherol is present in nature in only one form, RRR a-tocopherol. The chemical synthesis of a-tocopherol results in eight different forms (SRR, SSR, SRS, SSS, RSR, RRS, RSS, RRR), only one of which is RRR a-tocopherol. These forms differ in that they can be right (R) or left (S) at three different places in the a-tocopherol molecule. RRR a-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore the form of vitamin E found in the largest quantities in the blood and tissue. A protein synthesized in the liver (a-TTP alpha-tocopherol transfer protein) preferentially selects the natural form of vitamin E (RRR a-tocopherol) for distribution to the tissues. However, the mechanisms for the regulation of vitamin E in tissues are not known... 

Based upon theoretical considerations of the mechanisms of hypothermic-induced cellular injury, we developed the University of Wisconsin organ preservation solution (UW solution) that has had a widespread and dramatic effect on organ preservation (Table 2). Prior to the development of this solution, the liver and pancreas could be preserved for only four to six hours. Thus, there was a large time constraint on liver and pancreas transplantation and many cadaveric organs were wasted. However, the UW solution increased preservation duration to 48 to 72 hours, and dramatically increased the quality and numbers of these organs transplanted. Furthermore, this solution appears effective for the preservation of the kidney for three days and the heart for at least 15 hours. 

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