General liver metabolism

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. 

Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.39 Ciprofloxacin is about 50% cleared by... 

The authors concluded that the mixture induced effects on the liver and the kidney, and on the general metabolism at high doses but caused only minor effects on immune function, reproductive hormone levels, or general indices of reproductive function measures. The results suggested that additive or synergistic effects of exposure to contaminants resulting in residue levels representative of contemporary human tissue levels are unlikely to result in adverse effects on immune function or reproductive physiology in male rats. 

Vitamins are usually classified as either fat soluble (vitamins A, D, E, and K) or water soluble (vitamins B and C). The fat-soluble vitamins are generally metabolized slowly and are stored in the liver. In contrast, the water-soluble vitamins are rapidly metabolized and are readily excreted in the urine. 

There are several examples in the literature of the integration of studies with cDNA-expressed human P450 enzymes and human liver microsomes which have led to improved understanding of human enzyme-mediated activation of protoxins. Some of these examples are discussed below. Most of these reports have taken a multifaceted approach combining studies in human liver microsomes with cDNA-expressed enzymes. The general metabolic properties of these toxic xenobiotics (e.g. multiplicity of enzymes, differences in affinity and capacity, methods to compare to human liver data, etc.) apply to drugs and drug candidates as well. 

Sulfotransferase activity is not restricted to minoxidil. The ability of other pyrimidine-, as well as pyridine-, triazine- and imidazole N-oxides to serve as substrates was investigated using soluble liver preparation and PAPS. The variety of structures studied indicated that heteroaromatic N-oxides are generally metabolized by sulfotransferases183. Presumably, all of the heterocycles tested were conjugated via their N-oxide oxygens. 

In addition to these various actions on rather general metabolic functions, GH also has some very specific effects. It has a general stimulatory effect on protein synthesis but also stimulates synthesis of some proteins selectively. Predominant among these is somatomedin C/insulin-like growth factor I (Sm-C/IGF-I), production of which is stimulated markedly in many tissues, especially the liver [13,16]. 

Burger, M. M. and Madnick, H. M. (1983). General and liver-specific metastasis possible mechanisms. In Liver in Metabolic Diseases Proceedings of the 35th Falk Symposium, Basel, October 15-17, 1982 (Bianchi, L., Landmann, L., Gerok, W., Sickinger, K. and Stalder, G. A., eds.). MTP Press, Boston, pp. 351-365. 

MEK is rapidly absorbed by inhalation, skin contact and ingestion and transferred into the blood and other tissues. MEK is metabolized in the liver, mainly to 3-hydroxy-2-butanone and 2,3-butanediol that are eliminated in urine. Most MEK probably enters the general metabolism in the body and is converted to acetate that is eventually broken down to carbon dioxide and water that are then eliminated in exhaled air and urine. Small amounts of MEK itself are also eliminated in exhaled air and urine. MEK and its metabolites are mostly cleared from the body within 24 h, and MEK does not accumulate in the body. 

Certain benzidine-derived (direct azo) dyes afford, by reduction, generally metabolic degradation in the gut or fiver, the free aryl amine. The azo cleavage may be brought about by gut bacteria and mammalian fiver azo reductases. In 1978, the US National Institute of Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) reported that the benzidine-colorants Cl Direct Black 38, Cl Direct Blue 6 and Cl Direct Brown 95 were all reduced to 10a by rat liver in vivo, though trypan blue (35), Congo red (36) and Chicago sky blue were not. However, all six... 

Several TRK-850 derivatives were synthesized based on the general strategies mentioned above, and their metabolic stabilities were evaluated in the presence of human liver microsomes. Metabolic rates were determined by incubating the compounds with human liver microsomal enzymes and then quantifying the remaining parent peak by HPLC analysis. The data were expressed as the elimination rate constant (Kel) and the relative metabolic rate, or the /C , [ of the compound compared with the /C, [ of TRK-850 (ATF, ratio). 

The amino amide-type local anesthetics, however, are metabolized primarily in the liver, involving CYP1A2 isozymes (49). A general metabolic scheme for lidocaine is shown in Figure 16.10. 

Following ingestion of large amounts of zinc, increased levels are found in the heart, spleen, kidneys, liver, bone, and blood. It is not known if there is a relationship between the toxic effects observed in humans and tissue storage levels of zinc. Zinc stored in bone is not readily available to the general metabolic pool. During decreased calcium intake or bone resorption, zinc is released from the bone. It is not known if there are any toxic effects associated with this release of zinc. 

The conversion of acetoacetic acid to hydroxybutyric acid restitutes the 4-carbon compounds to the general metabolism because the liver contains enzymes that will activate jS-hydroxybutyric acid to yield j8-hydroxybutyric CoA, whereas acetoacetic acid cannot be acylated by the liver. 

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