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Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [ 11 C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC 50  = 0.469  μ M) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC 50  = 24.4 and 98.1  μ M, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC 50  = 69.8 and 106  μ M) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [ 11 C]-vorozole is binding to in the liver.

enzyme research

Determining the IC<sub>50</sub> Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver

Determining the IC50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver

Determining the IC₅₀ Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver