Detoxification metabolic

As mentioned in Section 5.3.2.3, extrapolation using allometric scaling based on metabolic rate assumes that the parent compound is the toxic agent and that the detoxification is related to the metabolic rate and thus controls the tissue level. This is relevant for oral exposure only. With regard to inhalation of substances, which act systemically, the lower detoxification (metabolic) rate in larger animals is balanced by a lower uptake (lower respiratory rate) and thus no scaling factor is needed (ECETOC 2003). 

Exposure studies have been made using mice and rats (257). These experiments have demonstrated species differences in butadiene toxicity and carcinogenicity. Butadiene was found to be a potent carcinogen in the mouse, but only a weak carcinogen in the rat. The interpretations have focused on differences in toxification rates and detoxification metabolisms as causative factors (257). The metabolism is believed to proceed through intermediates involving butadiene monoepoxide and butadiene diepoxide (257). A similar mechanism has been proposed for its biodegradation pathway (258). 

P16) (32,76)] hydrocarbons carcinogens, and detoxification metabolism. Arg554Lys polymorphism... 

Elderly individuals often develop adverse reactions to drugs at dosage levels well tolerated by younger persons. These reactions may be due to an age-related increase in sensitivity to drugs or impairment of detoxification (metabolism) and excretion functions. 

Matthews HB. 1982. Aryl halides. In Jakoby WB, Bend JR, Caldwell J, eds. Metabolic basis of detoxification. Metabolism of functional groups. New York Academic Press, 51-68. 

Triazine Resistance We attempted to answer the previous four questions using data and examples derived from the study of the best documented case of herbicide resistance, triazine resistance. Two kinds of mechanisms may be responsible for this triazine resistance first is the presence of detoxification metabolic pathways, as seen in corn (11). This also may occur in weed populations, especially Panicoideae, but a low heritability makes its study complex. The second mechanism of triazine resistance is the loss of herbicide binding at the level of the chloroplast. 

Table 2. Examples of Metabolic Detoxification and Metabolic Activation of Chemicals by Biological Systems...

The result of this biosynthesis is that the product is nicotinic acid mononucleotide rather than free nicotinic acid. Ingested nicotinic acid is converted to nicotinic acid mononucleotide which, in turn, is converted to nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide. If excess nicotinic acid is ingested, it is metabolized into a series of detoxification products (Fig. 4). Physiological metabohtes include /V-methylnicotinamide (19) and A/-methyl-6-pyridone-2-carboxamide (24) (1). 

Biocatalytic access to both antipodal sulfoxides was exploited in total syntheses of bioactive compounds, which is outlined in some representative examples. Biooxidation of functionalized dialkyl sulfides was utilized in the direct synthesis of both enantiomers of sulforaphane and some analogs in low to good yields and stereoselectivities (Scheme 9.27) [206]. This natural product originates from broccoli and represents a potent inducer of detoxification enzymes in mammalian metabolism it might be related to anticarcinogenic properties of plants from the cruciform family. All four possible stereoisomers of methionine (R = Me) and ethionine sulfoxides... 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

Volkow ND, Wang GJ, Overall JE, et al Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. Alcohol Clin Exp Res 21 1278-1284, 1997... 

Examples of differences in the responses of wildlife organisms to EDCs include the differences in sensitivity to phthalates and bisphenols among mollusks, crustaceans, and amphibians compared to fish. In invertebrates, biological effects are observed at exposures in the ng/L to low pg/L range, compared to high pg/L for most effects in fish (reviewed in Oehtmann et al. 2008). In addition, aquatic mollusks tend to bioconcentrate and bioaccumulate pollutants to a greater level than hsh, possibly owing to poorer capabilities for metabolic detoxification (see Chapter 4, Section 4.3). 

As illustrated in Table 43-5, the discovery of the nuclear receptor superfamily has led to an important understanding of how a variety of metabolites and xenobi-otics regulate gene expression and thus the metabolism, detoxification, and elimination of normal body products and exogenous agents such as pharmaceuticals. Not surprisingly, this area is a fertile field for investigation of new therapeutic interventions. 

Pool concentration of a substance that exceeds the threshold - for example megadose vitamin C - or substances that are excreted unchanged because they cannot be metabolised, such as sugar alcohols, or compounds that are not biologically essential, such as carcinogens, bacterial toxins and some minor plant constituents, are also bioavailable (and thus bioactive) in that they have a metabolic impact, even if this is only the stimulation of detoxification processes, or the use of energy for their excretion. 

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

The detoxification and metabolism of higher plants has been reviewed (Sandermann 1994), and a few examples are given below as illustration ... 

Munnecke DM, LM Johnson, HW Talbot, S Barik (1982) Microbial metabolism and enzymology of selected pesticides. In Biodegradation and Detoxification of Environmental Pollutants (Ed AM Chrakrabarty), pp. 1-32. CRC Press, Boca Raton, FL. 

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