Baseline Lipophilicity Relationships in Human Cytochromes P450 Associated with Drug Metabolism

Abstract

From analyses of human P450 substrates and their physicochemical properties, it is apparent that baseline lipophilicity relationships exist for over 70 substrates of eight drug-metabolizing P450 enzymes from families CYP1, CYP2, and CYP3. Equations of the general form shown below result in all cases investigated thus far:where a is the slope of the line which can be termed the hydrophobicity factor of the enzyme active site, possibly being related to the extent of hydrophobic amino acid residues lining the heme pocket; b is the intercept on the y axis and can be regarded as the sum of nonhydrophobic interactions between enzyme and substrate; ΔG_bind is the free energy change for substrate binding to P450, based on the relationshipwhere K_m is the Michaelis constant, and ΔG_part is the free energy change for partitioning between n-octanol and water based on the relationshipwhere P is the n-octanol/water partition coefficient. These findings facilitate the analysis of P450 enzyme-substrate binding interactions and provide information about the likely hydrophobic character of human P450 active site regions. This shows that there are common interactions for certain numbers of substrates in each case composed of hydrogen bonding and π–π stacking, the extent of which varies from one P450 enzyme to another.

Key Words :

• Lipophilicity
• Cytochromes P450
• Human drug metabolism