Metabolism cytochrome cavity

There are two main factors that determine the site of metabolism (i) the chemical reactivity and (ii) the preferred orientation of the compound inside the cytochrome cavity. A new technique called MetaSite [32] has been developed in order to consider at the same time, the substrate-cytochrome interaction and the chem-... 

The rate and the site of metabolism for xenobiotics are due to a complex mixture of recognition, shape and chemical reactivity. The human cytochrome P450 shape in proximity to the reactive heme plays a fundamental role in molecular recognition and orientation. Thus, the CYP cavity shape modulates the likelihood of a compound reacting with the enzyme, since it has to enter into the cavity, reach the reactive site (the heme), adopt a stable orientation to allow the reaction to occur and subsequently exit from the cavity. Different cytochromes show different cavity shape, and in silico prediction cannot neglect their key role. 

When healthy volunteers were exposed by inhalation to 100 or 400 ppm tetrahydrofuran in air, the percentage of expired tetrahydrofuran was 25-35%. The elimination half-life of tetrahydrofuran was 30 min in individuals exposed to 200 ppm for 3h. Some tetrahydrofuran is absorbed in the nasal cavity due to its solubility and inspiratory flow rate. Tetrahydrofuran uptake in the nasal tissue is dependent on its reaction with tissue substrates. Some tetrahydrofuran can be metabolized in the nasal cavity. Tetrahydrofuran blood concentrations were higher at 1 h postexposure than immediately after cessation of exposure. In vitro studies indicated that tetrahydrofuran was first hydroxylated by microsomal enzymes. High concentrations (lO molH ) of tetrahydrofuran inhibited the in vitro activity of rat hepatic cytochrome P450 by 80%. Tetrahydrofuran has been noted to enhance the toxic action of a number of compounds and stimulate the rapid absorption of reactive metabolites. Some of the tetrahydrofuran is excreted in the exhaled breath, while the various metabolites of tetrahydrofuran are excreted in the urine. 

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