Enzyme induction factors affecting

There are many factors, both chemical and biological, which affect the disposition of xenobiotics. Chemical factors include size and structure, pKa, chirality, and lipophilicity. Biological factors include species, sex and strain, genetic factors, hormonal influences, disease and pathological conditions, age, stress, diet, dose, enzyme induction and inhibition, and tissue and organ specificity. All of these factors can affect the toxicity of a chemical by changing its disposition, especially its metabolism. 

The pharmacologic principles of ligand-receptor interaction predict that the level of receptor should affect dose-response curves for enzyme induction. In rodent systems, several endogenous and exogenous factors have been shown to alter levels of various receptors or other components in the induction pathway. 

Table 2 illustrates the extraordinary range of human variation in the levels or activities of DMEs that are inducible. However, because factors other than induction also affect enzyme levels and activities, the ranges of variation listed in this table should not be taken as representing fold-induction nor should they be viewed as representing the range of inducibility for any particular enzyme. Some enzymes (e.g., CYP1A1) are virtually absent unless... 

Factors affecting the rate of synthesis include the level of induction or repression of the gene encoding the enzyme (see Topics G3 and G4 and also the rate of degradation of the mRNA produced from that gene. Many key enzymes at control points in metabolic pathways have particularly short-lived mRNAs and the rate of enzyme synthesis is thus readily controlled by factors that affect the rate of gene transcription. 

Environmental factors. Examples of these are co-administration of other drugs, which can affect the rate and extent of drug metabolism. This can become literally a matter of life and death as a number of potentially fatal drug interactions involve liver enzyme induction and competition for drug-metabolism enzymes. 

Section VI indicates that availability of nitrate at the induction and assimilation sites plays a major role in regulating the level of nitrate reductase and the in situ rate of reduction of nitrate. If this is valid, then factors that regulate the uptake, translocation, and entry of nitrate into the cytoplasm of cells of various plant organs have more significant effects on regulating enzyme induction and rate of nitrate assimilation throughout the life cycle of plants than other mechanisms that affect induction, inhibition, and assimilation. 

Elimination can be accomplished by passive diffusion when external concentrations are lower than internal concentrations favoring outward flux and by enzymatic pathways that convert hydrophobic parent compounds to more polar metabolites that can be more readily excreted by those taxa that possess a kidney or kidney-like organ (vertebrates and invertebrates such as annelids, molluscs, and arthropods). Conversion of the hydrophobic PAH to a more polar metabolite will decrease its ability to diffuse through the gill membrane, thus favoring the excretory route. The rate of elimination may be affected by environmental factors such as temperature and salinity, and by physiological factors, including reproductive state, age, sex, stress, and enzyme induction, in addition to such factors as route of uptake, chemical hydrophobicity, and exposure history. 

If the neurotoxicity of /7-hexane was potentiated in this study by co-exposure to acetone, the level of n-hexane alone required to produce these effects would be higher than 58 ppm and the MRL level would be higher. Results from simulations with a PBPK model that accurately predicted /7-hexane blood and 2,5-hexanedione urine levels (Perbellini et al. 1986, 1990a) indicate that at concentrations of 50 ppm, the rate-limiting factor in /7-hexane metabolism is delivery to the liver, not metabolic activity. This suggests that at this concentration (and at the MRL concentration of 0.6 ppm), induction of P-450 enzymes in the liver by acetone or other chemicals would not affect the rate at which 2,5-hexanedione was produced. 

As described in Section 4.3, CYP2B6 is regulated by CAR and PXR, which also are the two key regulators of CYP2C9 and CYP2C19. Circumstances that alter induction of any one of these three enzymes are likely to also affect the expression of other enzymes since they share many of the same regulatory factors. 

Fluoroaluminate complexes can mimic the action of many hormones, neurotransmitters, and growth factors. G-protein-mediated cell responses are key steps in neurotransmission and intercellular signaling in the brain [20], and TFA acts as an active stimulatory species [21]. Exposure of osteoblasts to TFA results in a marked potentiation of intracellular orthophosphate transport, alluding to the anion s ability to increase bone mineralization [22]. Brief exposure to aluminum fluoride complexes induces prolonged enhancement of synaptic transmission [23] and can potentially affect the activity of many other ion channels and enzymes in the kidney [24]. Rapid and dynamic changes of the cytoskeletal actin network are of vital importance to the motility of many cells, and TFA induction effects a pronounced and sustained... 

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