In the present work, gold nanoparticles coated chitosan/reduced graphene oxide (Au-CS-RG) was prepared for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 1A1 (CYP1A1) immobilization, investigation of the direct electrochemistry and electrochemically-driven drug metabolism. The immobilized CYP2D6 and CYP1A1 displayed respectively a pair of redox peaks with a formal potential of 492 4 and 504 6 my. The response showed a surface-controlled electrode process with an average electron transfer rate constant of 5.19 +/- 03 s(-1) for CYP2D6 and 3.24 +/- 0.4 s(-1) for CYP1A1 determined in the scan rate of 100 mV/s. When the Au-CS-RG was treated with polyacrylic acid (PAA), the resulting nanocomposites (PAA-Au-CS-RG) changed the surface charge of Au-CS-RG from positive to negative and increased the size of the coated gold nanoparticles from 15 to 25 nm. This led to negative-shift of the formal potential to -513 +/- 6 mV for CYP2D6 and -509 +/- 5 mV for CYP1A1, while the electron transfer rate constant decreased to 4.10 +/- 0.3 s(-1) for CYP2D6 and 2.78 +/- 0.2 s(-1) for CYP1A1, respectively. The immobilized CYP2D6 and CYP1A1 in both cases showed excellent electrochemically-driven drug metabolism. The LC-MS analysis demonstrated the bioconversion from tramadol or benzo[a]pyrene to o-demethyl-tramadol or 7.8-diol benzo[a]pyrene by the electrochemically-driven way, respectively. The metabolic inhibition of the quinidine and alpha-naphthoflavone to the enzymatic activity of CYP2D6 and CYP1A1 were also evaluated. (C) 2016 Elsevier B.V. All rights reserved.