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. 2020 Sep;374(3):438–451. doi: 10.1124/jpet.120.265868

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Fig. 3. — Reversible inhibition of CYP17A1 by abiraterone and D4A. Concentration-response plots represent the initial inhibited state (EI) of the CYP17A1-mediated 17α-hydroxylase and C17,20-lyase enzymatic reactions when slow-, tight-binding inhibitors (A and B) abiraterone and (E and F) D4A were introduced. The measured initial velocities () were used together with velocity of the uninhibited reaction () to calculate the fractional velocities across various concentrations of abiraterone and D4A (1–300 nM). Using eq. 2, apparent inhibition constants () for the initial CYP17A1-inhibitor encounter complexes were first obtained from the midpoint of isotherm curves. values were subsequently used in nonlinear regression analyses (eq. 3a) to determine the forward ( and reverse isomerization constants. Reversible inhibition experiments were also performed in the presence of multiple substrate (progesterone or 17α-hydroxypregnenolone) and (C and D) abiraterone or (G and H) D4A concentrations. To discern the mode of inhibition, Michaelis-Menten plots generated were subjected to double reciprocal transformations to yield Lineweaver-Burk graphs as presented in Supplemental Fig. 4. Based on the identified mode of inhibition, the inhibition constant for the initial EI complex ( could eventually be derived from . Each point represents the mean ± S.D. of triplicate determinations.

Inline graphic — Reversible inhibition of CYP17A1 by abiraterone and D4A. Concentration-response plots represent the initial inhibited state (EI) of the CYP17A1-mediated 17α-hydroxylase and C17,20-lyase enzymatic reactions when slow-, tight-binding inhibitors (A and B) abiraterone and (E and F) D4A were introduced. The measured initial velocities () were used together with velocity of the uninhibited reaction () to calculate the fractional velocities across various concentrations of abiraterone and D4A (1–300 nM). Using eq. 2, apparent inhibition constants () for the initial CYP17A1-inhibitor encounter complexes were first obtained from the midpoint of isotherm curves. values were subsequently used in nonlinear regression analyses (eq. 3a) to determine the forward ( and reverse isomerization constants. Reversible inhibition experiments were also performed in the presence of multiple substrate (progesterone or 17α-hydroxypregnenolone) and (C and D) abiraterone or (G and H) D4A concentrations. To discern the mode of inhibition, Michaelis-Menten plots generated were subjected to double reciprocal transformations to yield Lineweaver-Burk graphs as presented in Supplemental Fig. 4. Based on the identified mode of inhibition, the inhibition constant for the initial EI complex ( could eventually be derived from . Each point represents the mean ± S.D. of triplicate determinations.