Microsomal monooxygenases metabolism

The first step of this detannylation reaction sequence yields derivatives of increased toxicity and potency as inhibitors to mitochondrial respiration, whereas each subsequent step reduces the potency and alters the type of biological activity (Thayer, 1974). In the microsomal monooxygenase metabolism of trialkyltin acetate, carbon hydroxylation is the major biological oxidation reaction (Fish et al.,... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

The metabolism of permethrin will be taken more generally as an example of the metabolism of pyrethroids (Figure 12.2). The two types of primary metabolic attack are by microsomal monooxygenases and esterases. Monooxygenase attack involves... 

Walker, C.H. (1978). Species differences in microsomal monooxygenase activities and their relationship to biological half lives. Drug Metabolism Reviews 7(2), 295-323. 

Funari E, A Zoppinki, A Verdina, G de Angelis, L Vittozzi (1987) Xenobiotic metabolizing enzyme systems in test fish. I. Comparative studies of liver microsomal monooxygenases. Ecotoxicol Environ Saf 13 24-31. 

Also included in these in vivo studies were trials with the microsomal monooxygenase inhibitor, SKF 525-A. As in the cases of the susbtrates, no remarkable effects were observed. The fate of the inhibitor is unknown. To date, SKF 525-A exposures have not been coupled with measurements of oxidative metabolism. 

Dibromoethane is metabolized to active forms capable of inducing toxic effects by either of two systems-the microsomal monooxygenase system (cytochrome P-450 oxidation) and the cytosolic activation system (glutathione conjugation). Figure 2-3 provides an overview of the metabolism of... 

Once absorbed, 1,2-dibromoethane is rapidly metabolized. Its metabolism may induce effects by either of two systems, the microsomal monooxygenase system or the cytosolic activation system. Animal research has shown that seventy percent of 1,2-dibromoethane is excreted in the urine and feces within 48 hours. The lack of persistent metabolites in the tissues indicate that... 

The ability of PBBs to induce hepatic Phase I xenobiotic metabolizing enzymes (cytochrome P-450-dependent monooxygenases) is well documented (Dannan et al. 1978b, 1982a, 1982b, 1983 Ecobichon et al. 1979 Moore et al. 1978, 1979 Parkinson et al. 1983 Robertson et al. 1982 Schramm et al. 1985). PBB mixtures were classified as "mixed-type" inducers of hepatic microsomal monooxygenases and... 

Haake JM, Merrill JC, Safe S. 1985. The in vitro metabolism of benzo [ajpyrene by polychlorinated and polybrominated biphenyl induced rat hepatic microsomal monooxygenases. Can J Physiol Pharmacol 63 1096-1100. 

Adverse environmental conditions or stimuli, which create stress in an animal, may influence drug metabolism and disposition. Cold stress, for instance, increases aromatic hydroxylation, as does stress due to excessive noise. It should be noted that the microsomal monooxygenases show a diurnal rhythm in both rats and mice, with the greatest activity at the beginning of the dark phase. 

In both cases, metabolism by the microsomal monooxygenase enzymes occurs in which the sulfur atom attached to the phosphorus is replaced by an oxygen (chap. 5, Fig. 12). 

Imazu, K., Fujishiro, K. Inoue, N. (1992) Effects of dimethylformamide on hepatic microsomal monooxygenase system and glutathione metabolism in rats. Toxicology, ll. 41-50... 

Xenobiotics, in addition to serving as substrates for a number of enzymes, may also serve as inhibitors or inducers of these or other enzymes. Many examples are known of compounds that first inhibit and subsequently induce enzymes such as the microsomal monooxygenases. The situation is even further complicated by the fact that although some substances have an inherent toxicity and are detoxified in the body, others without inherent toxicity can be metabolically activated to potent toxicants. The following examples are illustrative of the situations that might occur involving two compounds ... 

Irreversible inhibition, which is much more important toxicologically, can arise from various causes. In most cases the formation of covalent or other stable bonds or the disruption of the enzyme structure is involved. In these cases the effect cannot be readily reversed in vitro by either dialysis or dilution. The formation of stable inhibitory complexes may involve the prior formation of a reactive intermediate that then interacts with the enzyme. An excellent example of this type of inhibition is the effect of the insecticide synergist piperonyl butoxide (Figure 9.6) on hepatic microsomal monooxygenase activity. This methylenedioxyphenyl compound can form a stable inhibitory complex that blocks CO binding to P450 and also prevents substrate oxidation. This complex results from the formation of a reactive intermediate, which is shown by the fact that the type of inhibition changes from competitive to irreversible as metabolism, in the... 

Reductase activities were only 30-35% of those in microsomes from unsupplemented male animals, the most profound decrease occurring in the low-fat-fed animals. Reductase is generally considered to be the rate-limiting component of the microsomal monooxygenase system and this decrease in activity could have profound effects on the metabolism of these foreign compounds. 

The proximate carcinogens arising from the metabolic activation of benzo(a)pyrene are isomers of benzo(a)pyrene 7,8-diol-9,10-epoxide (Figure 10.1C). These metabolites arise by prior formation of the 7,8-epoxide, which gives rise to the 7,8-dihydrodiol through the action of epoxide hydrolase. The diol is further metabolized by the microsomal monooxygenase system to the 7,8-diol-9,10-epoxides, which are both potent mutagens and unsuitable substrates for the further action of epoxide hydrolase. 

The metabolic pathways of diazinon are shown in Figure 8.26. Diazinon is mainly hydrolyzed to diethylthiophosphoric acid by cytochrome P450 monooxygenases and esterase (phosphatase). Diazinon is also oxidized by P450s to diazoxon. Microsomal monooxygenases also oxidize diazinon at the isopropyl group. The methyl group on the pyrimidine... 

Age effects in drug metabolism are illustrated in Figure 9.3, showing how the rabbit liver microsomes increase in activity with age. In this species, the level of microsomal monooxygenase activity in adults is reached in about 30 days. 

A good example of substrate specificity in enzyme action is the metabolism of juvenile hormone (JH) analogs by insects. In a series of experiments summarized in Table 9.7 to 9.10, the activity of esterases and microsomal monooxygenases from three dipterans against 12... 

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