Hepatic cellular metabolism

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

A number of experimental and clinical reports have suggested that a variety of factors unrelated to drug metabolism and direct hepatotoxicity may also influence susceptibility to DILL In addition, the nature of idiosyncratic liver injuries suggests that a majority of these reactions involve an immune mechanism. Hepatic cellular dysfunction and death have the ability to initiate immunological reactions, including both adaptive and innate immune responses. This inflammatory process has been implicated in the development of liver injury induced by such drugs as APAP, dihydralazine, and halothane (Laskin and Gardner 2003 Liu and Kaplowitz 2002 Luster et al. 2001). 

A method has been developed I or measurement of heat production rale on pieces of liver tissue with the aim to avoid eventual alterations of cellular metabolic processes during the cell preparation procedure 1108]. Samples, 5-8 mg, were taken from rats by aspiration needle biopsy. Oxygen consumption was measured at the same time. Sodium fluoride was used for inhibition of the anaerobic pathway. The metabolic aerobic/anaerobic profile showed a good qualitative agreement with the earlier studies on isolated hepatocytes. The results indicated that the technique used, with small liver samples, was suitable for studying overall metabolism of human hepatic tissue in different liver diseases. 

Both ADH and ALDH use NAD+ as cofactor in the oxidation of ethanol to acetaldehyde. The rate of alcohol metabolism is determined not only by the amount of ADH and ALDH2 enzyme in tissue and by their functional characteristics, but also by the concentrations of the cofactors NAD+ and NADH and of ethanol and acetaldehyde in the cellular compartments (i.e., cytosol and mitochondria). Environmental influences on elimination rate can occur through changes in the redox ratio of NAD+/NADH and through changes in hepatic blood flow. The equilib-... 

In addition to the well-known iron effects on peroxidative processes, there are also other mechanisms of iron-initiated free radical damage, one of them, the effect of iron ions on calcium metabolism. It has been shown that an increase in free cytosolic calcium may affect cellular redox balance. Stoyanovsky and Cederbaum [174] showed that in the presence of NADPH or ascorbic acid iron ions induced calcium release from liver microsomes. Calcium release occurred only under aerobic conditions and was inhibited by antioxidants Trolox C, glutathione, and ascorbate. It was suggested that the activation of calcium releasing channels by the redox cycling of iron ions may be an important factor in the stimulation of various hepatic disorders in humans with iron overload. 

There are data from animal studies in mice, rats, and pigs that indicate that both carbohydrate metabolism and lipid metabolism may be affected by exposure to heptachlor or heptachlor epoxide (Enan et al. 1982 Halacka et al. 1974 Kacew and Singhal 1973 Pelikan 1971). Alterations in gluconeogenic enzymes and an increase in cellular steatosis in the liver have been reported. Granulomas and fibrotic liver have also been observed. In addition, hepatocellular carcinoma was identified as causally related to heptachlor in the diet in a mouse study conducted by the National Cancer Institute (NCI 1977). The existing evidence suggests that heptachlor and heptachlor epoxide are hepatic toxicants. 

In the rabbit eye, a drop of the liquid caused superficial injury. The liquid on the belly of a rabbit caused a faint erythema of short duration. The toxic effects of acetonitrile are attributed to the metabolic release of cyanide via hepatic metabolism cyanide in turn acts by inhibiting cytochrome oxidase and thus impairs cellular respiration. Evidence of the cyanide effect is supported by the reported effectiveness of specific cyanide antidotes in acetonitrile poisonings. ... 

Diethanolamine is metabolized by biosynthetic routes common to endogenous alkanolamines (ethanolamine and choline) and incorporated into phospholipids. It is excreted predominantly unchanged with a half-life of approximately one week in urine. In the absence of sodium nitrite, no conversion to TV-nitrosodiethanolamine is observed. Diethanolamine competitively inhibits the cellular uptake of choline in vitro and hepatic changes in choline homeostasis, consistent with choline deficiency, are observed in vivo. 

APAP, although a safe drug in therapeutic doses, can lead to severe and potentially lethal liver and kidney injury in cases of overdose. Liver injury involves a characteristic centrilobular hepatic necrosis. The centrilobular region is rich in metabolic enzymes, such as the CYP family of isozymes. CYP2E1 is the predominant P450 isozyme in catalyzing the oxidation of APAP to a reactive intermediate, N-acetyl-p-benzoquinonimine (NAPQI), which possesses an electrophilic carbon that will covalently bind to cellular proteins [35], as shown in Scheme 3.2. 

PBBs and PBDEs may also cause toxicity by other mechanisms of action. For example, some PBB congeners can be metabolized to reactive arene oxides (Kohli and Safe 1976 Kohli et al. 1978) that may alkylate critical cellular macromolecules and result in injury. PBDEs may disrupt thyroid hormones by induction of hepatic microsomal UDPGT, which increases the rate of T4 conjugation and excretion, or by mimicking T4 or T3 PBDEs and their hydroxy metabolites are structurally similar to these thyroid hormones which are also hydroxy-halogenated diphenyl ethers (see Section 3.5.2). Clinical interventions designed to interfere with this mechanism or the metabolism of PBBs have yet to be developed. 

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