Inhaled glucorticoids (GC) therapies are commonly used in the treatment for chronic asthma, yet 30% of asthmatics demonstrate varying degrees of steroid insensitivity. GC are predominantly metabolized by the CYP3A class of cytochrome P450 enzymes which are expressed differentially in a tissue-specific manner. Commonly, GC metabolism is studied by hepatic CYP3A4 and not lung-specific CYP3A5. However, differential CYP3A expression and metabolism can alter target�tissue GC concentrations and thus efficacy. We have recently demonstrated that glucocorticoids are dehydrogenated by CYP3A enzymes to produce electrophilic 6,7-unsaturated products which are potentially toxic. Furthermore, we have identified the drug, Fluticasone�, as an efficient inactivator of lung specific CYP3A5. Here we have investigated the interaction of seven different commonly used GC with molecular dynamics refined experimental structures of CYP3A4 and homology models of CYP3A5 to identify key structural differences in CYP3A active sites that support the observed differential metabolism.

Investigation of the structural basis for the differential metabolism of glucocorticoids by CYP3A4 and CYP3A5 enzymes

245th National Meeting (2013)

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