Theoretical calculation of triazolam hydroxylation and endogenous steroid inhibition in the active site of CYP3A4.
Authors: Torimoto N, Ishii I, Hata M, Kobayashi Y, Nakamura H, Ariyoshi N, Kitada M
CYP3A4 has unusual kinetic characteristics because it has a large active site. CYP3A4 produced more 4-hydroxytriazolam than alpha-hydroxytriazolam at concentrations of more than 60 muM triazolam, and different steroids had different inhibitory effects on the system. To clarify these interesting observations, the interactions between substrate and substrate/steroid were investigated by theoretical calculations. When two triazolam molecules were docked into the active site, the distance between the O-atom and the 4-hydroxylated site was less than the distance to the alpha-hydroxylated site because of interaction between the two triazolam molecules. Estradiol inhibited both alpha- and 4-hydroxytriazolam fo...
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