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Các enzyme quan trọng trong Xúc tác phản ứng kích hoạt chuyển hóa Loại enzyme oxy hóa phản ứng cytochrome P450s Prostaglandin synthetase Flavin chứa monooxygenases Rượu và aldehyde Gut dehydrogenases Cytochromes Reductases P450 vi Glutathione transferases Sulfotransferases Glucuronidases Cysteine liên hợp S-β-lyase Gut vi, thủy phân | NATURE AND STABILITY OF REACTIVE METABOLITES 151 Table 8.1 Enzymes Important in Catalyzing Metabolic Activation Reactions Type of Reaction Enzyme Oxidation Cytochrome P450s Prostaglandin synthetase Flavin-containing monooxygenases Alcohol and aldehyde dehydrogenases Reduction Reductases Cytochromes P450 Gut microflora Conjugation Glutathione transferases Sulfotransferases Glucuronidases Deconjugation Hydrolysis Cysteine S-conjugate fi-lyase Gut microflora hydrolyses microflora may also lead to the formation of reactive toxic products. With some chemicals only one enzymatic reaction is involved whereas with other compounds several reactions often involving multiple pathways are necessary for the production of the ultimate reactive metabolite. 8.3 NATURE AND STABILITY OF REACTIVE METABOLITES Reactive metabolites include such diverse groups as epoxides quinones free radicals reactive oxygen species and unstable conjugates. Figure 8.2 gives some examples of activation reactions the reactive metabolites formed and the enzymes catalyzing their bioactivation. As a result of their high reactivity reactive metabolites are often considered to be short-lived. This is not always true however because reactive intermediates can be transported from one tissue to another where they may exert their deleterious effects. Thus reactive intermediates can be divided into several categories depending on their half-life under physiological conditions and how far they may be transported from the site of activation. 8.3.1 Ultra-short-lived Metabolites These are metabolites that bind primarily to the parent enzyme. This category includes substrates that form enzyme-bound intermediates that react with the active site of the enzyme. Such chemicals are known as suicide substrates. A number of compounds are known to react in this manner with CYP and such compounds are often used experimentally as CYP inhibitors see the discussion of piperonyl butoxide Section 7.2.2 . Other compounds although not
