Factors That Influence Metabolic Activation

In the European program COST (European CO-operation in the Field of Scientific and Technical Research) 8.41 Biological and Biochemical Diversity of Hydrogen Metabolism the main objective is to pool interrelated European expertise in order to understand the structural and molecular basis of the functions, as well as the factors that influence the activity and stability of hydrogenase enzymes. 

The major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Aluminium is the third most abundant element in the earth s crust and is used widely in the manufacture of construction materials, wiring, packaging materials and cookware. The metal and its compounds are used in the paper, glass and textile industries as well as in food additives. Despite the abundance of the metal, its chemical nature effectively excludes it from normal metabolic processes. This is due largely to the low solubility of aluminium silicates, phosphates and oxides that result in the aluminium being chemically unavailable. However, it can cause toxic effects when there are raised concentrations of aluminium in water used for renal dialysis. These effects are not seen when aluminium is at the concentrations usually present in drinking water. There is currently much activity to examine the factors that influence uptake of aluminium from the diet. 

Because several of the metabolites of vitamin D3 are biologically active, the molecular species of vitamin D3 which passes into the yolk cannot be determined just from measurement of antirachitic activity. Consequently, a reliable and sensitive method for determining the amount of the unchanged form of vitamin D3 would be extremely beneficial to those interested in the metabolism and other factors that influence the chicken to deposit vitamin D3 in... 

The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Section 3.3), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2.6) as a solid or suspension. 

Renwick examined the nature of the UFs generally applied for intraspecies and interspecies extrapolations. He proposed the division of each of these UFs into subfactors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The toxicokinetic considerations include absorption, distribution, metabolism, and excretion of a toxic compound, and therefore address differences in the amount of the parent compound or active metabolite available to the target organ(s). The toxicodynamic considerations are based on variations in the inherent sensitivity of a species or individual to chemical-induced toxicity, and may result from differences in host factors that influence the toxic response of a target organ to a specified dose. The advantage to such a subdivision is that components of these UFs... 

In addition to SREBPs, several members of the nuclear receptor superfamily regulate lipid metabolism. Nuclear receptors are transcription factors that are generally activated when bound to specific small-molecule ligands (Chapter 11). Certain nuclear receptors influence whole-body lipid metabolism by regulating the absorption of dietary lipids, cellular synthesis of lipids, transport protein-mediated import and export of lipids, levels of lipoproteins and their receptors, and catabolism of lipids (e.g., fatty acid oxidation in the peroxisome) and their secretion from the body. 

Analysis of the biochemical aspects of organ specificity in toxic action (by Dr. J. S. Dutcher) began with a survey of the factors that influence patterns of organ-specific toxicity. Notable among these are the mechanisms of detoxication and metabolic activation, leading to covalent interaction with cellular macromolecules and consequent toxicity. 

In the current study, many factors that influence bone metabolism were altered by beef fat and CLA. The exception was ex vivo PGE2 production in tibia, which was not influenced by the lower level of CLA given to rats in this study. Interestingly, supplemental CLA at the dietary level of inclusion reduced serum osteocalcin in rats after 84 d of dietary treatment. Moreover, serum BALP activity... 

Another important factor that influences on the accuracy of models is a metabolic pathway or metabohc activation of the parent compound which is not usually considered. It would be reasonable to predict the first reactive metabolite or find an actnal proof that it is produced, and then make a separate prediction for the metabolite of interest. Several computer programs provide either the prediction of htunan metabolism or common metabolic pathway based on the rules extracted from several species of mammals (rat, mouse, hitman, hamster), using a mixture of in vitro and in vivo metabohsm data of compoimds [68, 89]. However, in these programs, predictions made for the possible reactive metabolites do not affect the prediction for a parent compoimd. 

Factors that affect drug metabolism will influence the development of serious adverse effects. TPMT, one of the three enzymes that metabolize 6-MP, is encoded by a gene on chromosome 6 that contains functional polymorphisms. Multiple variants have been described ( 2, 3A, 3B, 3C, 3D, 4, 5, 6, 7, 10 31,32) that result in lower TPMT activity, leading to preferential metabolism of 6-MP by the HGPRT enzyme. This results in an increase in the amount of cytotoxic thioguanine nucleotides and greater myelotoxicity. There appears to be an allele dose-dependent... 

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