Association of Human Cytochrome P450 1A1 (CYP1A1) and Sulfotransferase 1A1 (SULT1A1) Polymorphisms with Differential Metabolism and Cytotoxicity of Aminoflavone

Abstract

Aminoflavone (AF), a clinically investigational novel anticancer agent, requires sequential metabolic activation by CYP1A1 and SULT1A1 to exert its antitumor activities. The purpose of this study was to determine the functional significance of common polymorphisms of human CYP1A1 and SULT1A1 on the metabolism and cytotoxicity of AF. To this end, Chinese Hamster V79 cells were genetically engineered to stably express human CYP1A1*1 (wild-type), CYP1A1*2C (I462V), or CYP1A1*4 (T461N) and coexpress human CYP1A1*1 with human SULT1A1*1 (wild-type), SULT1A1*2 (R213H), or SULT1A1*3 (M223V). The metabolism and cytotoxicity of AF were evaluated in these cellular models. All common variants of CYP1A1 and SULT1A1 were actively involved in the metabolic activation of AF, but with a varying degree of activity. Whereas CYP1A1 I462V variant exhibited a superior activity (mainly caused by a significantly higher V(max)) for hydroxylations of AF, expression of different CYP1A1 variants did not confer cell differential sensitivity to AF. The cells coexpressing CYP1A1*1 with SULT1A1*1, SULT1A1*2, or SULT1A1*3 displayed SULT1A1 allele-specific sensitivity to AF: SULT1A1*3 exhibited the highest sensitivity (IC(50), 0.01 μmol/L), followed by SULT1A1*1 (IC(50), 0.5 μmol/L), and SULT1A1*2 showed the lowest sensitivity (IC(50), 4.4 μmol/L). These data suggest that the presence of low-activity SULT1A1*2 may predict poor response to AF, whereas the presence of high-activity CYP1A1/SULT1A1 alleles, especially combination of CYP1A1*2C and SULT1A1*3 or SULT1A1*1, may be beneficial to patients receiving AF. The present study provides a foundation for future clinical investigations of potential genetic biomarkers that may enable selection of patients for the greatest potential benefit from AF treatment.